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Cited by 526Iron Metabolism and DisordersNeurological diseases and metabolismFerroptosis and cancer prognosis

Intracellular iron transport and storage: from molecular mechanisms to health implications

Open access
Mackenzie, Elizabeth L., Iwasaki, Kenta, Tsuji, Yoshiaki·2008·Antioxidants & Redox Signaling
DOI 10.1089/ars.2007.1893PMC PMC2932529
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Abstract

Maintenance of proper "labile iron" levels is a critical component in preserving homeostasis. Iron is a vital element that is a constituent of a number of important macromolecules, including those involved in energy production, respiration, DNA synthesis, and metabolism; however, excess "labile iron" is potentially detrimental to the cell or organism or both because of its propensity to participate in oxidation-reduction reactions that generate harmful free radicals. Because of this dual nature, elaborate systems tightly control the concentration of available iron. Perturbation of normal physiologic iron concentrations may be both a cause and a consequence of cellular damage and disease states. This review highlights the molecular mechanisms responsible for regulation of iron absorption, transport, and storage through the roles of key regulatory proteins, including ferroportin, hepcidin, ferritin, and frataxin. In addition, we present an overview of the relation between iron regulation and oxidative stress and we discuss the role of functional iron overload in the pathogenesis of hemochromatosis, neurodegeneration, and inflammation.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes molecular mechanisms controlling intracellular iron transport and storage, emphasizing ferroportin, hepcidin, ferritin, and frataxin, and links dysregulation to hemochromatosis, neurodegeneration, and inflammation. It argues that labile iron must be tightly controlled because iron is essential but can drive Fenton chemistry and oxidative damage.

Key findings

  • Iron is essential for oxygen transport, oxidative phosphorylation, DNA biosynthesis, and xenobiotic metabolism, but excess labile iron generates reactive oxygen species via the Fenton reaction; ∼25 mg of iron is needed daily for erythropoiesis and other vital functions, while only 1 to 2 mg comes from intestinal sources, making storage and recycling critical.
  • Ferritin is the major iron-storage protein: it consists of 24 heavy and light subunits and can sequester 4,500 iron atoms; the H subunit has ferroxidase activity that converts Fe2+ to Fe3+ for storage, and cytoplasmic, mitochondrial, nuclear, and serum ferritin forms have distinct features.
  • Ferroportin is the only known iron exporter; hepcidin negatively regulates it by binding and triggering internalization and degradation. Hepcidin is a 25-amino-acid peptide whose expression is increased by iron and inflammation and decreased by hypoxia and anemia.
  • Frataxin deficiency causes Friedreich ataxia, most commonly (96% to 98%) from homozygous GAA repeat expansion; prevalence is estimated at 1 in 50,000 among whites, with normal individuals having fewer than 35 repeats and patients ranging from 100 to >1,000 repeats. Frataxin is involved in iron–sulfur cluster biosynthesis, heme synthesis, and mitochondrial iron homeostasis.

Methods

  • Narrative review; no primary experiments are reported. The paper synthesizes published literature on intracellular iron transport, storage, regulation, and disease.
  • It covers molecular mechanisms including transferrin/transferrin receptor, DMT1, ferroportin, hepcidin, ferritin, and frataxin, and discusses hereditary hemochromatosis types 1–4, neurodegeneration, and inflammation.
  • Main analysis is qualitative integration of cited studies, tables, and models; no systematic search strategy or meta-analysis is described.

Limitations

  • Stated: many mechanisms remain unclear, including the exact function of HFE in TfR1 regulation, how C/EBPα participates in global iron sensing and hepcidin regulation, crosstalk between lysosome- and proteasome-mediated ferritin degradation, sources and physiologic function/regulation of serum ferritin, and whether oxidative damage is tightly associated with FRDA pathophysiology.
  • Evident: as a narrative review, it lacks systematic search/inclusion criteria and quantitative synthesis; conclusions depend on cited literature and may reflect selection or interpretation bias.
  • Evident: no primary data or new experimental validation are presented; disease associations are largely correlative.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1089/ars.2007.1893

Cites

352 of 352 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 473 cited sources checked · 0 supported · 0 flagged

  • Premisenone given
    § I. Introduction

    Excess iron systemically and at the cellular level leads to deleterious effects including free radical-induced damage to cells, cellular components, tissues, and organs.

    “Likewise, an excess of iron systemically and at the cellular level leads to deleterious effects including free radical-induced damage to cells, cellular components, tissues, and organs.”
    Quote in the paperNot a substantial claim
  • Premisecitation
    § I. Introduction

    Deviations from normal iron levels have been indicated in the pathogenesis of aging, neurodegenerative disease, cancer, and infection.

    “Deviations from normal iron levels have been indicated in the pathogenesis of aging, neurodegenerative disease, cancer, and infection (18, 23, 156, 180, 299, 334).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • Premisecitation
    § Abstract

    Excess labile iron is potentially detrimental to the cell or organism because it participates in oxidation-reduction reactions that generate harmful free radicals.

    “excess “labile iron” is potentially detrimental to the cell or organism or both because of its propensity to participate in oxidation–reduction reactions that generate harmful free radicals”
    • Also stated in: § I. Introduction · plain
      “This propensity to undergo oxidation-reduction reactions is also responsible for the toxicity of iron (229).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Papanikolaou G. Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol. 2005;202:199–211. doi: 10.1016/j.taap.2004.06.021. [DOI] [PubMed] [Google Scholar] source

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  • Premisecitation
    § II. Iron Transport

    Iron binding and release by Tf are coordinated by a conformational change in which the two subdomains of each lobe open, and the N1, N2, C1, and C2 domains twist.

    “Iron binding and release are coordinated by a conformational change in which the two subdomains of each lobe open, and the N1, N2, C1, and C2 domains twist (114, 115).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [114] Grossmann JG. Neu M. Evans RW. Lindley PF. Appel H. Hasnain SS. Metal-induced conformational changes in transferrins. J Mol Biol. 1993;229:585–590. doi: 10.1006/jmbi.1993.1063. [DOI] [PubMed] [Google Scholar] source

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  • Premisecitation
    § II. Iron Transport

    In nonintestinal cells, circulating iron is bound to transferrin and imported via receptor-mediated endocytosis after binding to the transferrin receptor.

    “In nonintestinal cells, circulating iron is bound to transferrin (Tf) and is imported via receptor-mediated endocytosis after binding to the transferrin receptor (TfR) (249).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • May combine two claims. 159
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    Premisecitation
    § I. Introduction

    When ferrous iron interacts with H2O2, it undergoes the Fenton reaction, producing ferric iron, hydroxyl radical, and may result in peroxidation of adjacent lipids and oxidative damage to DNA and other macromolecules.

    “when ferrous iron interacts with H2O2, it undergoes the Fenton reaction (229). The Fenton reaction produces ferric iron, −OH, and the hydroxyl radical. It may also result in the peroxidation of adjacent lipids and lead to oxidative damage of DNA and other macromolecules.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Papanikolaou G. Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol. 2005;202:199–211. doi: 10.1016/j.taap.2004.06.021. [DOI] [PubMed] [Google Scholar] source

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    • Rests on an assumption: Most cytoplasmic iron is in its reduced (ferrous) form.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § II. Iron Transport

    Each of the homologous amino domains of Tf binds one atom of Fe3+.

    “Each of the homologous amino domains binds one atom of Fe3+.”
    Quote in the paperNot a substantial claim

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    Premisereasoning
    § I. Introduction

    Both severe iron overload and iron deficiency may be deleterious.

    “In conjunction with this dichromatic nature, both severe iron overload and iron deficiency may be deleterious.”
    Quote in the paperSubstantial claim

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    Premisereasoning
    § I. Introduction

    Iron deficiency causes cell damage, reduction of cell growth and proliferation, hypoxia, and death.

    “iron deficiency is a serious problem that causes cell damage, reduction of cell growth and proliferation, hypoxia, and death.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § II. Iron Transport

    Tf serves as a storage sink for sequestering iron extracellularly until iron is needed, then allowing it to reach target tissues.

    “In this sense, Tf serves as a storage sink for sequestering iron extracellularly until iron is needed, and then allowing it to reach target tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § II. Iron Transport

    The change in pH in the endosome causes iron to disassociate from Tf, and it is then exported from the endosome into the cytosol by a divalent metal transporter after reduction of iron by a ferric reductase.

    “The change in pH in the endosome causes the iron to disassociate from Tf, and it is then exported from the endosome into the cytosol by a divalent metal transporter after reduction of iron by a ferric reductase”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § II. Iron Transport

    TfR2 is not redundant for TfR1, for TfR1 knockout is embryonically lethal despite the presence of TfR2.

    “Furthermore, TfR2 is not redundant for TfR1, for TfR1 knockout is embryonically lethal (184), despite the presence of TfR2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § II. Iron Transport

    HCP1 is abundantly expressed on the brush border of enterocytes in the duodenum, the primary location of intestinal iron absorption, and appears to mediate cellular heme uptake.

    “This protein, named heme carrier protein 1 (HCP1), is abundantly expressed on the brush border of enterocytes in the duodenum, the primary location of intestinal iron absorption, and it appears to mediate cellular heme uptake (Fig. 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [277] Shayeghi M. Latunde-Dada GO. Oakhill JS. Laftah AH. Takeuchi K. Halliday N. Khan Y. Warley A. McCann FE. Hider RC. Frazer DM. Anderson GJ. Vulpe CD. Simpson RJ. McKie AT. Identification of an intestinal heme transporter. Cell. 2005;122:789–801. doi: 10.1016/j.cell.2005.06.025. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § II. Iron Transport

    TfR1 deficiency results in low tissue iron levels, whereas TfR2 inadequacy leads to the development of hemochromatosis.

    “Deficiencies in TfR1 and TfR2 have different phenotypic outcomes: TfR1 deficiency results in low tissue iron levels, whereas TfR2 inadequacy leads to the development of hemochromatosis (34, 89).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Camaschella C. Roetto A. Cali A. De Gobbi M. Garozzo G. Carella M. Majorano N. Totaro A. Gasparini P. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14–15. doi: 10.1038/75534. [DOI] [PubMed] [Google Scholar]

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    Premisenone given
    § II. Iron Transport

    Two different TfRs, TfR1 and TfR2, are expressed and serve as gatekeepers for iron-bound Tf.

    “Two different TfRs, TfR1 and TfR2, are expressed and serve as gatekeepers for iron-bound Tf (Fe-Tf) (Fig. 1).”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § II. Iron Transport

    Unlike TfR1, TfR2 does not contain an IRE in its mRNA and does not appear to be regulated in an iron-dependent manner.

    “Unlike TfR1, TfR2 does not contain an IRE in its mRNA and does not appear to be regulated in an iron-dependent manner (90, 315).”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation
    § II. Iron Transport

    IRP2 is degraded in conditions of iron excess via a 73-amino acid domain called the iron-dependent degradation domain, which seems to be required for IRP2 degradation after protein oxidation by iron.

    “IRP2 is degraded in conditions of iron excess, via a 73–amino acid domain called the iron-dependent degradation domain, which seems to be required for IRP2 degradation after protein oxidation by iron (140, 141).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation
    § II. Iron Transport

    Stable overexpression of HFE in Chinese hamster ovary cells resulted in lower levels of TfR-mediated cellular iron uptake and decreased intracellular iron concentration.

    “Stable overexpression of HFE in Chinese hamster ovary cells resulted in lower levels of TfR-mediated cellular iron uptake and decreased intracellular iron concentration (314).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation
    § II. Iron Transport

    During heme-mediated gene regulation, heme induces IRP2 oxidation on Cys201, which is followed by enhanced IRP2 degradation.

    “For example, during heme-mediated gene regulation, heme induces IRP2 oxidation on Cys201, which is followed by enhanced IRP2 degradation (328).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § II. Iron Transport

    Five IREs are located in the 3′ UTR of TfR1, allowing the binding of IRP during iron-deficient conditions to stabilize the mRNA, thereby causing upregulation of TfR1.

    “Five IREs are located in the 3′ UTR of TfR1, allowing the binding of IRP during iron-deficient conditions to stabilize the mRNA, thereby causing upregulation of TfR1 (41, 211).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Interpretationnone given
    § II. Iron Transport

    NTBI appears to be primarily absorbed by the liver and may contribute to cellular iron loading.

    “This NTBI appears to be primarily absorbed by the liver and may contribute to cellular iron loading.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § II. Iron Transport

    Overexpression of murine Zip14 resulted in increased uptake of Fe2+ by HEK293 cells, whereas decreased Zip14 expression by siRNA decreased iron accumulation in murine hepatocyte AML12 cells.

    “Overexpression of murine Zip14 resulted in increased uptake of Fe2+ by HEK293 cells, whereas decreased Zip14 expression by siRNA decreased iron accumulation in murine hepatocyte, AML12 cells (188).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Liuzzi JP. Aydemir F. Nam H. Knutson MD. Cousins RJ. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci U S A. 2006;103:13612–13617. doi: 10.1073/pnas.0606424103. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Interpretationreasoning
    § II. Iron Transport

    TfR1 and TfR2 are differentially regulated and thereby may serve diverse roles in terms of iron sensing and regulation.

    “These results suggest that TfR1 and TfR2 are differentially regulated and thereby may serve diverse roles in terms of iron sensing and regulation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § II. Iron Transport

    Heme iron is obtained from meat sources and is more readily absorbed than nonheme iron obtained from consumption of grains and vegetables.

    “Heme iron is obtained from meat sources and is more readily absorbed than nonheme iron obtained from consumption of grains and vegetables.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § II. Iron Transport

    DMT1 expression was increased by an iron-deficient diet, and it was highly expressed in the rat duodenum.

    “Its expression was increased by an iron-deficient diet, and it was highly expressed in the rat duodenum.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § I. Regulation of divalent metal transporter 1

    Fpn is abundantly expressed on the basolateral membrane of polarized enterocytes in the duodenum, in the cytosol of reticuloendothelial cells, and on the basal surface of syncytiotrophoblasts of the placenta.

    “Simultaneous studies characterized Fpn, which is abundantly expressed on the basolateral membrane of polarized enterocytes in the duodenum, in the cytosol of reticuloendothelial cells, and on the basal surface of syncytiotrophoblasts of the placenta (1, 72, 198).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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      Not checked in the free run.

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    Premisecitation
    § I. Regulation of divalent metal transporter 1

    The DMT1B promoter contains a putative NF-κB element, and NF-κB bound to this response element during differentiation.

    “The DMT1B promoter contains a putative NF-κB element, and NF-κB bound to this response element during differentiation (231).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation
    § I. Regulation of divalent metal transporter 1

    In humans, deficiency in Cp results in aceruloplasminemia, which leads to late-onset degeneration of the retina and basal ganglia because of pathologic accumulation of iron in various tissues, including liver, spleen, and pancreas.

    “In humans, deficiency in Cp results in a disease called aceruloplasminemia, which leads to late-onset degeneration of the retina and basal ganglia because of the pathologic accumulation of iron in various tissues, including the aforementioned affected tissues as well as the liver, spleen, and pancreas (106).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § I. Regulation of divalent metal transporter 1

    DMT1A is expressed mainly in the duodenum and in epithelial cells, whereas DMT1B is expressed predominantly in erythroid cells.

    “DMT1A is expressed mainly in the duodenum and in epithelial cells, whereas DMT1B is expressed predominantly in erythroid cells (38, 39).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation
    § I. Regulation of divalent metal transporter 1

    Mutations in the Fpn gene may cause autosomal dominant hemochromatosis; a missense mutation (A77D), proposed to lead to Fpn haploinsufficiency, was shown to be related to an iron-overloaded phenotype.

    “Mutations in this gene may cause autosomal dominant hemochromatosis; a missense mutation (A77D), which was proposed to lead to Fpn haploinsufficiency, was shown to be related to an iron-overloaded phenotype (205).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § I. Regulation of divalent metal transporter 1

    Increased nitric oxide levels during retinoic acid-induced differentiation of P19 cells resulted in the downregulation of both DMT+IRE and DMT-IRE isoforms as well as DMT1B, but not DMT1A.

    “Increased nitric oxide levels during retinoic acid-induced differentiation of P19 cells resulted in the downregulation of both DMT+IRE and DMT-IRE isoforms as well as DMT1B, but not DMT1A (231).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Paradkar PN. Roth JA. Post-translational and transcriptional regulation of DMT1 during P19 embryonic carcinoma cell differentiation by retinoic acid. Biochem J. 2006;394:173–183. doi: 10.1042/BJ20051296. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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    Premisecitation
    § I. Regulation of divalent metal transporter 1

    Cp has ferroxidase activity and catalyzes the oxidation of Fe2+ to Fe3+.

    “Years later, it was revealed that Cp has ferroxidase activity and catalyzes the oxidation of Fe2+ to Fe3+ (228) (see Fig. 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims.

    Premisecitation
    § I. Regulation of divalent metal transporter 1

    Cp-knockout mice are normal at birth, but progressively accumulate iron, leading to a prominent elevation of iron content in the liver and spleen.

    “Cp-knockout mice are normal at birth, but progressively accumulate iron, leading to a prominent elevation of iron content in the liver and spleen (123).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Harris ZL. Durley AP. Man TK. Gitlin JD. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci U S A. 1999;96:10812–10817. doi: 10.1073/pnas.96.19.10812. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § I. Regulation of divalent metal transporter 1

    Fpn was originally identified by positional cloning to identify the causative gene for hypochromic anemia of weissherbst mutant zebrafish.

    “Fpn (also termed Ireg1, MTP1) was originally identified by positional cloning to identify the causative gene for hypochromic anemia of “weissherbst” mutant zebrafish (72).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Donovan A. Brownlie A. Zhou Y. Shepard J. Pratt SJ. Moynihan J. Paw BH. Drejer A. Barut B. Zapata A. Law TC. Brugnara C. Lux SE. Pinkus GS. Pinkus JL. Kingsley PD. Palis J. Fleming MD. Andrews NC. Zon LI. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403:776–781. doi: 10.1038/35001596. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § II. Iron Transport

    An endosomal ferric reductase, Steap3, was identified and shown to colocalize with TfR1 and DMT1; its deletion was associated with the nm1054 mouse, which has hypochromic microcytic anemia caused by a defect in Fe-Tf cycle.

    “Recently, an endosomal ferric reductase, Steap3, was identified (222). It was shown to colocalize with TfR1 and DMT1, and furthermore, its deletion was associated with the nm1054 mouse, which has hypochromic microcytic anemia caused by a defect in Fe-Tf cycle (221, 222).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [221] Ohgami RS. Campagna DR. Antiochos B. Wood EB. Sharp JJ. Barker JE. Fleming MD. nm1054: a spontaneous, recessive, hypochromic, microcytic anemia mutation in the mouse. Blood. 2005;106:3625–3631. doi: 10.1182/blood-2005-01-0379. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [222] Ohgami RS. Campagna DR. Greer EL. Antiochos B. McDonald A. Chen J. Sharp JJ. Fujiwara Y. Barker JE. Fleming MD. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37:1264–1269. doi: 10.1038/ng1658. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisenone given
    § II. Iron Transport

    At normal physiologic concentrations, nonheme iron does not readily cross a plasma membrane via passive diffusion; instead, it must be actively transported.

    “at normal physiologic concentrations, nonheme iron does not readily cross a plasma membrane via passive diffusion; instead, it must be actively transported.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § I. Regulation of divalent metal transporter 1

    DMT1A appears to be mostly localized to the apical membrane of polarized intestinal epithelial cells, and thus may play an important role in systemic iron absorption through the intestine, whereas DMT1B is more broadly expressed and also localized to erythroid cells, suggesting that it may play a more widespread role in iron transport.

    “DMT1A appears to be mostly localized to the apical membrane of polarized intestinal epithelial cells, and thus may play an important role in systemic iron absorption through the intestine, whereas DMT1B is more broadly expressed and also localized to erythroid cells (38, 39), suggesting that it may play a more widespread role in iron transport”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Canonne-Hergaux F. Gruenheid S. Ponka P. Gros P. Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood. 1999;93:4406–4417. [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [39] Canonne-Hergaux F. Zhang AS. Ponka P. Gros P. Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Blood. 2001;98:3823–3830. doi: 10.1182/blood.v98.13.3823. [DOI] [PubMed] [Google Scholar]

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    Hepcidin is synthesized by the liver as an 84-amino acid precursor, processed and secreted as a final 25-amino acid peptide.

    “Hepcidin is synthesized by the liver as an 84–amino acid precursor, which is processed and then secreted as a final 25–amino acid peptide (232).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Park CH. Valore EV. Waring AJ. Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–7810. doi: 10.1074/jbc.M008922200. [DOI] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    The N-terminus of hepcidin is critical to the negative regulation of Fpn; deletion of all five N-terminal amino acids completely abrogated hypoferremia.

    “The N-terminus of hepcidin is critical to the negative regulation of Fpn; deletion of all five of the amino acids of the N-terminus completely abrogated the hypoferremia (213).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [213] Nemeth E. Preza GC. Jung CL. Kaplan J. Waring AJ. Ganz T. The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood. 2006;107:328–333. doi: 10.1182/blood-2005-05-2049. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    HFE2 is a BMP coreceptor, and its mutation suppresses BMP signaling.

    “HFE2 is a BMP coreceptor, and its mutation suppresses BMP signaling (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Babitt JL. Huang FW. Wrighting DM. Xia Y. Sidis Y. Samad TA. Campagna JA. Chung RT. Schneyer AL. Woolf CJ. Andrews NC. Lin HY. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–539. doi: 10.1038/ng1777. [DOI] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Interpretationreasoning
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    In conditions of iron depletion, the translation of Fpn is decreased, resulting in a decrease in iron export.

    “Thus, in conditions of iron depletion, the translation of Fpn is decreased, resulting in a decrease in iron export.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    The hepcidin promoter contains several C/EBP consensus sequences, and HNF4 and STAT motifs have been identified in DNA encoding hepcidin.

    “The hepcidin promoter contains several CCAAT/enhancer-binding protein (C/EBP) consensus sequences. In addition, hepatocyte nuclear factor 4 and signal transducer and activator of transcription (STAT) motifs have also been identified in DNA encoding hepcidin (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Courselaud B. Pigeon C. Inoue Y. Inoue J. Gonzalez FJ. Leroyer P. Gilot D. Boudjema K. Guguen-Guillouzo C. Brissot P. Loreal O. Ilyin G. C/EBPalpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism: cross-talk between C/EBP pathway and iron metabolism. J Biol Chem. 2002;277:41163–41170. doi: 10.1074/jbc.M202653200. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    Treatment of primary human hepatocytes with LPS increased hepcidin mRNA, and anti-IL-6 antibodies abrogated this induction.

    “The researchers treated primary human hepatocytes with LPS, observed an increase in hepcidin mRNA, and were able to abrogate the induction of hepcidin mRNA by treatment with anti-IL-6 antibodies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Nemeth E. Rivera S. Gabayan V. Keller C. Taudorf S. Pedersen BK. Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–1276. doi: 10.1172/JCI20945. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    When Cp is absent, Fe2+ remains bound to Fpn, leading to ubiquitination on Fpn Lys253.

    “when Cp was absent, Fe2+ remained bound to Fpn, leading to ubiquitination on Fpn Lys253 (65).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] De Domenico I. Ward DM. di Patti MC. Jeong SY. David S. Musci G. Kaplan J. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 2007;26:2823–2831. doi: 10.1038/sj.emboj.7601735. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    IL-6-knockout mice did not increase hepcidin mRNA in response to turpentine and did not show a decrease in serum iron.

    “IL-6-knockout mice did not increase hepcidin mRNA in response to turpentine, another stimulus causing inflammation, and correspondingly, they did not show a decrease in serum iron (214).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Nemeth E. Rivera S. Gabayan V. Keller C. Taudorf S. Pedersen BK. Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–1276. doi: 10.1172/JCI20945. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    Fpn degradation is abrogated by oxidation, depletion of extracellular Fe2+, or mutation of Lys253 to Ala.

    “Fpn degradation is abrogated by oxidation, depletion of extracellular Fe2+, or mutation of Lys253 to Ala (65).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] De Domenico I. Ward DM. di Patti MC. Jeong SY. David S. Musci G. Kaplan J. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 2007;26:2823–2831. doi: 10.1038/sj.emboj.7601735. [DOI] [PMC free article] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    Once inside the cell, Fpn is ubiquitinated after dephosphorylation and ultimately degraded in the lysosome.

    “Once inside the cell, Fpn is ubiquitinated after dephosphorylation, and ultimately, Fpn undergoes degradation in the lysosome (Fig. 6) (66).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] De Domenico I. Ward DM. Langelier C. Vaughn MB. Nemeth E. Sundquist WI. Ganz T. Musci G. Kaplan J. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007;18:2569–2578. doi: 10.1091/mbc.E07-01-0060. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § III. Iron Storage and Ferritin

    H expression is abundant in the heart, whereas the L subunit is predominant in the liver and spleen.

    “H expression is abundant in the heart, whereas the L subunit is predominant in the liver and spleen (125).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Harrison PM. Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275:161–203. doi: 10.1016/0005-2728(96)00022-9. [DOI] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § III. Iron Storage and Ferritin

    Ferritin H-deficient mice synthesize ferritins consisting of only L-subunit homopolymers, which lack ferroxidase activity and have lower iron-incorporation capability.

    “the synthesized ferritins consist of only L-subunit homopolymers (85), which lack ferroxidase activity and has lower iron-incorporation capability (183).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [85] Ferreira C. Bucchini D. Martin ME. Levi S. Arosio P. Grand-champ B. Beaumont C. Early embryonic lethality of H ferritin gene deletion in mice. J Biol Chem. 2000;275:3021–3024. doi: 10.1074/jbc.275.5.3021. [DOI] [PubMed] [Google Scholar] source

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    • cites [183] Levi S. Girelli D. Perrone F. Pasti M. Beaumont C. Corrocher R. Albertini A. Arosio P. Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome. Blood. 1998;91:4180–4187. [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    Hepatocytes and liver samples from mice with deleted VHL were iron deficient and showed increased expression of Fpn.

    “hepatocytes and liver samples from mice with deleted von Hip-pel-Lindau (VHL), which is the negative regulator of HIF-1, were iron deficient and showed increased expression of Fpn (Fig. 7) (242).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [242] Peyssonnaux C. Zinkernagel AS. Schuepbach RA. Rankin E. Vaulont S. Haase VH. Nizet V. Johnson RS. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs) J Clin Invest. 2007;117:1926–1932. doi: 10.1172/JCI31370. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § III. Iron Storage and Ferritin

    Oligodendrocytes have equal amounts of both H and L subunits, microglia express L-rich ferritin, and neurons have H-subunit abundant ferritin.

    “Oligodendrocytes have equal amounts of both H and L subunits, whereas microglia express L-rich ferritin, and neurons have H-subunit abundant ferritin (206, 333).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [206] Moos T. Morgan EH. The metabolism of neuronal iron and its pathogenic role in neurological disease: review. Ann N Y Acad Sci. 2004;1012:14–26. doi: 10.1196/annals.1306.002. [DOI] [PubMed] [Google Scholar] source

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    • cites [333] Zecca L. Stroppolo A. Gatti A. Tampellini D. Toscani M. Gallorini M. Giaveri G. Arosio P. Santambrogio P. Fariello RG. Karatekin E. Kleinman MH. Turro N. Hornykiewicz O. Zucca FA. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci U S A. 2004;101:9843–9848. doi: 10.1073/pnas.0403495101. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § III. Iron Storage and Ferritin

    Ferritin H is induced by NF-κB in response to TNF-α treatment, resulting in suppression of ROS and inhibition of apoptosis.

    “Ferritin H is induced by NF-κB in response to TNF-α treatment, resulting in suppression of ROS and inhibition of apoptosis (243).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [243] Pham CG. Bubici C. Zazzeroni F. Papa S. Jones J. Alvarez K. Jayawardena S. De Smaele E. Cong R. Beaumont C. Torti FM. Torti SV. Franzoso G. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell. 2004;119:529–542. doi: 10.1016/j.cell.2004.10.017. [DOI] [PubMed] [Google Scholar] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § III. Iron Storage and Ferritin

    Ferritin H and L subunits are encoded by two different genes.

    “Ferritin H and L subunits are encoded by two different genes (322).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [322] Worwood M. Brook JD. Cragg SJ. Hellkuhl B. Jones BM. Perera P. Roberts SH. Shaw DJ. Assignment of human ferritin genes to chromosomes 11 and 19q13.3–––19qter. Hum Genet. 1985;69:371–374. doi: 10.1007/BF00291657. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    Smad4-knockout mice had lower levels of hepcidin and did not induce hepcidin in response to iron loading or IL-6 stimulation.

    “Smad4-knockout mice had lower levels of hepcidin and did not induce hepcidin in response to iron loading or IL-6 stimulation (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Babitt JL. Huang FW. Wrighting DM. Xia Y. Sidis Y. Samad TA. Campagna JA. Chung RT. Schneyer AL. Woolf CJ. Andrews NC. Lin HY. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–539. doi: 10.1038/ng1777. [DOI] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § III. Iron Storage and Ferritin

    The ferritin L subunit stabilizes ferritin structure and facilitates the uptake of iron into the shell.

    “the ferritin L subunit stabilizes ferritin structure and facilitates the uptake of iron into the shell (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Arosio P. Levi S. Ferritin, iron homeostasis, and oxidative damage. Free Radic Biol Med. 2002;33:457–463. doi: 10.1016/s0891-5849(02)00842-0. [DOI] [PubMed] [Google Scholar]

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  • May combine two claims.

    Premisecitation
    § III. Iron Storage and Ferritin

    Cytoplasmic ferritin consists of 24 subunits of heavy and light chains in various ratios and can sequester 4,500 iron atoms.

    “This ubiquitous protein consists of 24 subunits of heavy (H) and light (L) chains in various ratios and can sequester 4,500 iron atoms (125).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Harrison PM. Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275:161–203. doi: 10.1016/0005-2728(96)00022-9. [DOI] [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § L. Ferroportin and hephaestin cooperate in iron efflux from intestinal cells

    Administration of soluble HJV inhibited BMP-mediated induction of hepcidin and resulted in increased levels of Fpn in vivo.

    “administration of soluble HJV inhibited BMP-mediated induction of hepcidin and resulted in increased levels of Fpn in vivo (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Babitt JL. Huang FW. Xia Y. Sidis Y. Andrews NC. Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117:1933–1939. doi: 10.1172/JCI31342. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Serum ferritin and ferritin receptor

    Serum ferritin has been thought to reflect the iron stores in the body and to increase as a secreted byproduct of intracellular ferritin synthesis.

    “Serum ferritin has been thought to reflect the iron stores in the body and to increase as a secreted byproduct of intracellular ferritin synthesis (250, 297).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [250] Prieto J. Barry M. Sherlock S. Serum ferritin in patients with iron overload and with acute and chronic liver diseases. Gastroenterology. 1975;68:525–533. [PubMed] [Google Scholar] source

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    • cites [297] Tran TN. Eubanks SK. Schaffer KJ. Zhou CY. Linder MC. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood. 1997;90:4979–4986. [PubMed] [Google Scholar] source

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  • May combine two claims.

    Premisecitation
    § C. Serum ferritin and ferritin receptor

    Ferritin binds to erythroid precursors, brain tissue, and placental microvilli membranes.

    “Several studies showed that ferritin also binds to erythroid precursors (100), brain tissue (138), and placental microvilli membranes (186).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [100] Gelvan D. Fibach E. Meyron-Holtz EG. Konijn AM. Ferritin uptake by human erythroid precursors is a regulated iron uptake pathway. Blood. 1996;88:3200–3207. [PubMed] [Google Scholar] source

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    • cites [138] Hulet SW. Powers S. Connor JR. Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains. J Neurol Sci. 1999;165:48–55. doi: 10.1016/s0022-510x(99)00077-5. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [186] Liao QK. Kong PA. Gao J. Li FY. Qian ZM. Expression of ferritin receptor in placental microvilli membrane in pregnant women with different iron status at mid-term gestation. Eur J Clin Nutr. 2001;55:651–656. doi: 10.1038/sj.ejcn.1601195. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Serum ferritin and ferritin receptor

    The structure of mitochondrial ferritin was determined at 1.38 angstrom resolution and is very similar to that of ferritin H, with about 80% homology in amino acid sequences.

    “The structure of mitochondrial ferritin was determined at 1.38 angstrom resolution and was very similar to that of ferritin H, with ∼80% homology in the amino acid sequences (172).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Langlois d'Estaintot B. Santambrogio P. Granier T. Gallois B. Chevalier JM. Precigoux G. Levi S. Arosio P. Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala. J Mol Biol. 2004;340:277–293. doi: 10.1016/j.jmb.2004.04.036. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Serum ferritin and ferritin receptor

    Serum ferritin is identical to cytoplasmic ferritin, but the primary component of serum ferritin is the ferritin L subunit, which contains little iron.

    “Serum ferritin is identical to cytoplasmic ferritin, but the primary component of serum ferritin is the ferritin L subunit, which contains little iron (323).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [323] Worwood M. Dawkins S. Wagstaff M. Jacobs A. The purification and properties of ferritin from human serum. Biochem J. 1976;157:97–103. doi: 10.1042/bj1570097. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Serum ferritin and ferritin receptor

    Mitochondrial ferritin expression is highest in testis; other tissue has very little expression.

    “The highest expression level was observed in testis; other tissue has very little expression (74, 182).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [74] Drysdale J. Arosio P. Invernizzi R. Cazzola M. Volz A. Corsi B. Biasiotto G. Levi S. Mitochondrial ferritin: a new player in iron metabolism. Blood Cells Mol Dis. 2002;29:376–383. doi: 10.1006/bcmd.2002.0577. [DOI] [PubMed] [Google Scholar] source

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    • cites [182] Levi S. Corsi B. Bosisio M. Invernizzi R. Volz A. Sanford D. Arosio P. Drysdale J. A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem. 2001;276:24437–24440. doi: 10.1074/jbc.C100141200. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Serum ferritin and ferritin receptor

    Mitochondrial ferritin is encoded by an unusual intronless gene on chromosome 5q23.1 that encodes a 242-amino acid precursor of a ferritin H-like protein with a 60-amino acid N-terminal leader sequence for mitochondrial import.

    “Mitochondrial ferritin was originally reported as an unusual intronless gene on chromosome 5q23.1 that encodes a 242–amino acid precursor of a ferritin H-like protein, which has a long N-terminal leader sequence with 60 amino acids for mitochondrial import (182).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] Levi S. Corsi B. Bosisio M. Invernizzi R. Volz A. Sanford D. Arosio P. Drysdale J. A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem. 2001;276:24437–24440. doi: 10.1074/jbc.C100141200. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § III. Iron Storage and Ferritin

    Lysosome-mediated ferritin degradation uses the autophagy system under particular conditions and iron chelator treatment.

    “Lysosome-mediated ferritin degradation uses the autophagy system under particular conditions (173, 226) and iron chelator treatment (165)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [173] Larson JA. Howie HL. So M. Neisseria meningitidis accelerates ferritin degradation in host epithelial cells to yield an essential iron source. Mol Microbiol. 2004;53:807–820. doi: 10.1111/j.1365-2958.2004.04169.x. [DOI] [PubMed] [Google Scholar]

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    • cites [226] Ollinger K. Roberg K. Nutrient deprivation of cultured rat hepatocytes increases the desferrioxamine-available iron pool and augments the sensitivity to hydrogen peroxide. J Biol Chem. 1997;272:23707–23711. doi: 10.1074/jbc.272.38.23707. [DOI] [PubMed] [Google Scholar] source

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    • cites [165] Konijn AM. Glickstein H. Vaisman B. Meyron-Holtz EG. Slotki IN. Cabantchik ZI. The cellular labile iron pool and intracellular ferritin in K562 cells. Blood. 1999;94:2128–2134. [PubMed] [Google Scholar]

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    § III. Iron Storage and Ferritin

    Amino acid and serum depletion activate autophagy, resulting in ferritin degradation, which sensitized cells to H2O2-induced oxidative stress.

    “Amino acid and serum depletion activate autophagy, resulting in ferritin degradation, which sensitized cells to H2O2-induced oxidative stress because of an increased “labile iron” pool, which caused ROS production via the Fenton reaction (226).”
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    • cites [226] Ollinger K. Roberg K. Nutrient deprivation of cultured rat hepatocytes increases the desferrioxamine-available iron pool and augments the sensitivity to hydrogen peroxide. J Biol Chem. 1997;272:23707–23711. doi: 10.1074/jbc.272.38.23707. [DOI] [PubMed] [Google Scholar] source

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    § III. Iron Storage and Ferritin

    Fpn expression enhances ferritin degradation via a proteasomal degradation-dependent pathway, because proteasome inhibitors prevented ferritin degradation.

    “It appears that Fpn expression enhances ferritin degradation via a proteasomal degradation-dependent pathway, because proteasome inhibitors treatment prevented ferritin degradation (64).”
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    • cites [64] De Domenico I. Vaughn MB. Li L. Bagley D. Musci G. Ward DM. Kaplan J. Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome. EMBO J. 2006;25:5396–5404. doi: 10.1038/sj.emboj.7601409. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    § C. Serum ferritin and ferritin receptor

    Ferritoid is a 30-kDa protein consisting of 270 amino acids specifically expressed in corneal epithelial cells.

    “Ferritoid is a 30-kDa protein consisting of 270 amino acids specifically expressed in corneal epithelial cells (201).”
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    • cites [201] Millholland JM. Fitch JM. Cai CX. Gibney EP. Beazley KE. Linsenmayer TF. Ferritoid, a tissue-specific nuclear transport protein for ferritin in corneal epithelial cells. J Biol Chem. 2003;278:23963–23970. doi: 10.1074/jbc.M210050200. [DOI] [PubMed] [Google Scholar] source

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    § IV. Regulation of Ferritin

    IRP2-knockout mice showed abnormal induction of ferritin expression, resulting in iron misregulation in intestinal mucosa and the CNS.

    “IRP2-knockout mice showed abnormal induction of ferritin expression, resulting in iron misregulation in intestinal mucosa and the CNS (55, 200).”
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    • cites [55] Cooperman SS. Meyron-Holtz EG. Olivierre-Wilson H. Ghosh MC. McConnell JP. Rouault TA. Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2. Blood. 2005;106:1084–1091. doi: 10.1182/blood-2004-12-4703. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [200] Meyron-Holtz EG. Ghosh MC. Iwai K. LaVaute T. Brazzolotto X. Berger UV. Land W. Ollivierre-Wilson H. Grinberg A. Love P. Rouault TA. Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J. 2004;23:386–395. doi: 10.1038/sj.emboj.7600041. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    § C. Serum ferritin and ferritin receptor

    Nuclear ferritin is glycosylated, with three potential glycosylation sites in the N-terminal region (Thr1, Thr2, Ser4) of ferritin H, whereas ferritin L contains only one (Ser2).

    “Nuclear ferritin was found to be glycosylated, and three potential glycosylation sites were identified in the N-terminal region (Thr1, Thr2, and Ser4) of ferritin H, whereas the ferritin L subunit appeared to contain only one (Ser2) (285).”
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    • cites [285] Surguladze N. Patton S. Cozzi A. Fried MG. Connor JR. Characterization of nuclear ferritin and mechanism of translocation. Biochem J. 2005;388:731–740. doi: 10.1042/BJ20041853. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    § IV. Regulation of Ferritin

    Iron binding to IRP1 competes with IRP1-IRE interaction, so increased iron levels enhance translation of ferritin proteins.

    “iron binding to IRP1 competes with IRP1–IRE interaction, so that increased iron levels in cells enhances translation of ferritin proteins (317).”
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    • cites [317] Walden WE. Selezneva AI. Dupuy J. Volbeda A. Fontecilla-Camps JC. Theil EC. Volz K. Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA. Science. 2006;314:1903–1908. doi: 10.1126/science.1133116. [DOI] [PubMed] [Google Scholar]

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    § C. Serum ferritin and ferritin receptor

    Binding of mutant ferritin H to DNA was lower and less effective for protection of DNA from UV damage.

    “the binding of this mutant ferritin H to DNA was lower and less effective for the protection of DNA from UV damage”
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    • cites [292] Thompson KJ. Fried MG. Ye Z. Boyer P. Connor JR. Regulation, mechanisms and proposed function of ferritin translocation to cell nuclei. J Cell Sci. 2002;115:2165–2177. doi: 10.1242/jcs.115.10.2165. [DOI] [PubMed] [Google Scholar] source

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    § C. Serum ferritin and ferritin receptor

    Nuclear ferritin is produced from the same mRNA as cytosolic ferritin and is composed predominantly of ferritin H.

    “Nuclear ferritin is produced from the same mRNA as cytosolic ferritin and is composed predominantly of ferritin H”
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    • cites [31] Cai CX. Birk DE. Linsenmayer TF. Ferritin is a developmentally regulated nuclear protein of avian corneal epithelial cells. J Biol Chem. 1997;272:12831–12839. doi: 10.1074/jbc.272.19.12831. [DOI] [PubMed] [Google Scholar]

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    • cites [32] Cai CX. Birk DE. Linsenmayer TF. Nuclear ferritin protects DNA from UV damage in corneal epithelial cells. Mol Biol Cell. 1998;9:1037–1051. doi: 10.1091/mbc.9.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    § IV. Regulation of Ferritin

    PMA induces IRP1 and IRP2 phosphorylation and enhances binding to ferritin IRE, resulting in decreased ferritin expression during PMA-induced HL-60 differentiation.

    “PMA induces IRP1 and IRP2 phosphorylation and enhances this binding to ferritin IRE, resulting in decreased ferritin expression during PMA induced HL-60 differentiation (269).”
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    • cites [269] Schalinske KL. Eisenstein RS. Phosphorylation and activation of both iron regulatory proteins 1 and 2 in HL-60 cells. J Biol Chem. 1996;271:7168–7176. doi: 10.1074/jbc.271.12.7168. [DOI] [PubMed] [Google Scholar] source

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    § IV. Regulation of Ferritin

    H2O2-induced oxidative stress and PMA modulate the activity of IRP1 and IRP2.

    “H2O2-induced oxidative stress and phorbol 12-myristate 13-acetate (PMA) have been shown to modulate the activity of IRP1 and IRP2 (269).”
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    • cites [269] Schalinske KL. Eisenstein RS. Phosphorylation and activation of both iron regulatory proteins 1 and 2 in HL-60 cells. J Biol Chem. 1996;271:7168–7176. doi: 10.1074/jbc.271.12.7168. [DOI] [PubMed] [Google Scholar] source

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    § IV. Regulation of Ferritin

    Ferritin H translation is transiently repressed by H2O2 treatment, in which IRP1 binding to ferritin H IRE is increased.

    “Ferritin H translation was also shown to be transiently repressed by H2O2 treatment, in which IRP1 binding to the ferritin H IRE is increased (33, 303).”
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    • cites [33] Caltagirone A. Weiss G. Pantopoulos K. Modulation of cellular iron metabolism by hydrogen peroxide: effects of H2O2 on the expression and function of iron-responsive element-containing mRNAs in B6 fibroblasts. J Biol Chem. 2001;276:19738–19745. doi: 10.1074/jbc.M100245200. [DOI] [PubMed] [Google Scholar]

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    • cites [303] Tsuji Y. Ayaki H. Whitman SP. Morrow CS. Torti SV. Torti FM. Coordinate transcriptional and translational regulation of ferritin in response to oxidative stress. Mol Cell Biol. 2000;20:5818–5827. doi: 10.1128/mcb.20.16.5818-5827.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    § IV. Regulation of Ferritin

    PIAS3 is an ATF1-binding partner and reverses ATF1-mediated ferritin H ARE repression by blocking ATF1 binding to the ARE.

    “protein inhibitor of activated STAT3 (PIAS3) was identified as an ATF1-binding partner and was shown to reverse ATF1-mediated ferritin H ARE repression by blocking ATF1 binding to the ARE (142).”
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    • cites [142] Iwasaki K. Hailemariam K. Tsuji Y. PIAS3 interacts with ATF1 and regulates the human ferritin H gene through an antioxidant-responsive element. J Biol Chem. 2007;282:22335–22343. doi: 10.1074/jbc.M701477200. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    § C. Ferritin transcriptional regulation by cytokines

    All NF-Y subunits A, B, and C were required for binding to DNA; at least the NF-YA subunit was required to activate the ferritin H gene in response to hemin treatment during differentiation of monocytes to macrophages.

    “All NF-Y subunits, A, B, and C, were required for binding to DNA; then at least the NF-YA subunit was required to activate the ferritin H gene in response to hemin treatment during differentiation of monocytes to macrophages (194).”
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    • cites [194] Marziali G. Perrotti E. Ilari R. Testa U. Coccia EM. Battistini A. Transcriptional regulation of the ferritin heavy-chain gene: the activity of the CCAAT binding factor NF-Y is modulated in heme-treated Friend leukemia cells and during monocyte-to-macrophage differentiation. Mol Cell Biol. 1997;17:1387–1395. doi: 10.1128/mcb.17.3.1387. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    § IV. Regulation of Ferritin

    tBHQ, sulforaphane, hemin, and high levels of iron activated the human ferritin L ARE.

    “tBHQ, sulforaphane, hemin, and high levels of iron activated this element (133)”
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    • cites [133] Hintze KJ. Theil EC. DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression. Proc Natl Acad Sci U S A. 2005;102:15048–15052. doi: 10.1073/pnas.0505148102. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    § IV. Regulation of Ferritin

    JunD is involved in transcriptional activation of the human ferritin H gene via the ARE during treatment of HepG2 cells with H2O2 or tBHQ, with JunD phosphorylation at Ser-100 induced.

    “JunD was also involved in the transcriptional activation of the human ferritin H gene via the ARE during treatment of HepG2 hepatocarcinoma cells with H2O2 or tert-butylhydroquinone (tBHQ), in which JunD phosphorylation at Ser-100 was induced (301).”
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    • cites [301] Tsuji Y. JunD activates transcription of the human ferritin H gene through an antioxidant response element during oxidative stress. Oncogene. 2005;24:7567–7578. doi: 10.1038/sj.onc.1208901. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    § C. Ferritin transcriptional regulation by cytokines

    NF-κB is activated by TNF-α and induces mouse and human ferritin H.

    “NF-κB is activated by TNF-α and has been shown to induce mouse and human ferritin H (171, 243).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [171] Kwak EL. Larochelle DA. Beaumont C. Torti SV. Torti FM. Role for NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J Biol Chem. 1995;270:15285–15293. doi: 10.1074/jbc.270.25.15285. [DOI] [PubMed] [Google Scholar] source

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    • cites [243] Pham CG. Bubici C. Zazzeroni F. Papa S. Jones J. Alvarez K. Jayawardena S. De Smaele E. Cong R. Beaumont C. Torti FM. Torti SV. Franzoso G. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell. 2004;119:529–542. doi: 10.1016/j.cell.2004.10.017. [DOI] [PubMed] [Google Scholar] source

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    § C. Ferritin transcriptional regulation by cytokines

    The proximal region of the human ferritin H gene was activated by NF-Y and p300 during hemin-induced FLC differentiation, and this proximal region was also responsible for cAMP.

    “The proximal region of the human ferritin H gene was activated by NF-Y and p300 during hemin-induced FLC differentiation, and this proximal region was also responsible for cAMP (80, 194, 248).”
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    • cites [80] Faniello MC. Bevilacqua MA. Condorelli G. de Crombrugghe B. Maity SN. Avvedimento VE. Cimino F. Costanzo F. The B subunit of the CAAT-binding factor NFY binds the central segment of the Co-activator p300. J Biol Chem. 1999;274:7623–7626. doi: 10.1074/jbc.274.12.7623. [DOI] [PubMed] [Google Scholar]

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    • cites [194] Marziali G. Perrotti E. Ilari R. Testa U. Coccia EM. Battistini A. Transcriptional regulation of the ferritin heavy-chain gene: the activity of the CCAAT binding factor NF-Y is modulated in heme-treated Friend leukemia cells and during monocyte-to-macrophage differentiation. Mol Cell Biol. 1997;17:1387–1395. doi: 10.1128/mcb.17.3.1387. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    • cites [248] Pilz RB. Impaired erythroid-specific gene expression in cAMP-dependent protein kinase-deficient murine erythroleukemia cells. J Biol Chem. 1993;268:20252–20258. [PubMed] [Google Scholar] source

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    § C. Ferritin transcriptional regulation by cytokines

    This activation mechanism was achieved by interaction of the NF-Y B subunit with p300/CBP; formation of this protein complex was enhanced by cAMP treatment.

    “This activation mechanism was achieved by interaction of the NF-Y B subunit with p300/CBP; formation of this protein complex was enhanced by cAMP treatment (80)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Faniello MC. Bevilacqua MA. Condorelli G. de Crombrugghe B. Maity SN. Avvedimento VE. Cimino F. Costanzo F. The B subunit of the CAAT-binding factor NFY binds the central segment of the Co-activator p300. J Biol Chem. 1999;274:7623–7626. doi: 10.1074/jbc.274.12.7623. [DOI] [PubMed] [Google Scholar]

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    § IV. Regulation of Ferritin

    Nrf2 disruption in mice enhanced susceptibility to severe airway inflammation, asthma, and cigarette smoke-induced emphysema.

    “Nrf2 disruption in mice enhanced susceptibility to severe airway inflammation, asthma, and cigarette smoke–induced emphysema (253, 254)”
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    • cites [253] Rangasamy T. Cho CY. Thimmulappa RK. Zhen L. Srisuma SS. Kensler TW. Yamamoto M. Petrache I. Tuder RM. Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest. 2004;114:1248–1259. doi: 10.1172/JCI21146. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [254] Rangasamy T. Guo J. Mitzner WA. Roman J. Singh A. Fryer AD. Yamamoto M. Kensler TW. Tuder RM. Georas SN. Biswal S. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005;202:47–59. doi: 10.1084/jem.20050538. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    § IV. Regulation of Ferritin

    Nrf2-knockout mice developed normally and survived to adult stage.

    “Nrf2-knockout mice developed normally and survived to adult stage”
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    • cites [45] Chan K. Lu R. Chang JC. Kan YW. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci U S A. 1996;93:13943–13948. doi: 10.1073/pnas.93.24.13943. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    § V. Frataxin and Iron Homeostasis

    Frataxin is involved in iron-sulfur cluster biosynthesis and mitochondrial iron homeostasis.

    “Although the primary function of frataxin is still elusive, it has been unveiled by various biochemical and genetic approaches that frataxin is involved in iron–sulfur cluster (ISC) biosynthesis and mitochondrial iron homeostasis.”
    Quote in the paperSubstantial claim

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    § V. Frataxin and Iron Homeostasis

    Frataxin is a nuclear-encoded mitochondrial protein conserved from yeast to human, but with no homology with proteins of known functional domains.

    “Frataxin is a nuclear-encoded mitochondrial protein conserved from yeast to human (166), but with no homology with proteins of known functional domains.”
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    • cites [166] Koutnikova H. Campuzano V. Foury F. Dolle P. Cazzalini O. Koenig M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet. 1997;16:345–351. doi: 10.1038/ng0897-345. [DOI] [PubMed] [Google Scholar] source

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    § V. Frataxin and Iron Homeostasis

    Yeast mature frataxin directly binds iron, and iron triggers assembly of frataxin oligomerization.

    “It was demonstrated that yeast mature frataxin directly binds iron (2), in which iron triggers assembly of frataxin oligomerization.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Adamec J. Rusnak F. Owen WG. Naylor S. Benson LM. Gacy AM. Isaya G. Iron-dependent self-assembly of recombinant yeast frataxin: implications for Friedreich ataxia. Am J Hum Genet. 2000;67:549–562. doi: 10.1086/303056. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    § V. Frataxin and Iron Homeostasis

    Disruption of yeast frataxin homologue YFH1 in yeast strain Δyfh1 induced accumulation of iron in mitochondria and enhanced sensitivity to oxidative stress by H2O2 and iron overload.

    “For instance, the disruption of the yeast frataxin homologue (YFH1) in yeast strain (Δyfh1) induced an accumulation of iron in mitochondria and enhanced their sensitivity to oxidative stress (by H2O2 and iron overload) (13, 93).”
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    • cites [13] Babcock M. de Silva D. Oaks R. Davis-Kaplan S. Jiralerspong S. Montermini L. Pandolfo M. Kaplan J. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science. 1997;276:1709–1712. doi: 10.1126/science.276.5319.1709. [DOI] [PubMed] [Google Scholar] source

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    • cites [93] Foury F. Cazzalini O. Deletion of the yeast homologue of the human gene associated with Friedreich's ataxia elicits iron accumulation in mitochondria. FEBS Lett. 1997;411:373–377. doi: 10.1016/s0014-5793(97)00734-5. [DOI] [PubMed] [Google Scholar] source

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    § V. Frataxin and Iron Homeostasis

    Frataxin-overexpressing mice showed normal iron metabolism with no signs of abnormalities.

    “The same research group generated frataxin-overexpressing mice, which also showed normal iron metabolism with no signs of abnormalities (203).”
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    • cites [203] Miranda CJ. Santos MM. Ohshima K. Tessaro M. Sequeiros J. Pandolfo M. Frataxin overexpressing mice. FEBS Lett. 2004;572:281–288. doi: 10.1016/j.febslet.2004.07.022. [DOI] [PubMed] [Google Scholar]

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    § V. Frataxin and Iron Homeostasis

    Deletion of yeast frataxin homologue YFH1 caused mitochondrial iron accumulation and increased sensitivity to H2O2 toxicity.

    “The first evidence of frataxin's role in mitochondrial iron regulation was obtained by deletion of yeast frataxin homologue, YFH1, and characterization of the yeast phenotype, which revealed that the deletion of YFH1 caused mitochondrial iron accumulation and increased sensitivity to H2O2 toxicity (13).”
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    • cites [13] Babcock M. de Silva D. Oaks R. Davis-Kaplan S. Jiralerspong S. Montermini L. Pandolfo M. Kaplan J. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science. 1997;276:1709–1712. doi: 10.1126/science.276.5319.1709. [DOI] [PubMed] [Google Scholar] source

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    § V. Frataxin and Iron Homeostasis

    In a mouse FRDA model, antioxidants (MnSOD mimetic or CuZnSOD overexpression) had no beneficial effect on FRDA cardiomyopathy, with absence of increased oxidative stress or decreased SOD expression in FRDA mouse tissues.

    “Furthermore, in a mouse FRDA model, antioxidants (MnSOD mimetic or CuZnSOD overexpression) had no beneficial effect on the FRDA cardiomyopathy, along with the evidence for the absence of increased oxidative stress or decreased SOD expression in FRDA mouse tissues (273).”
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    • cites [273] Seznec H. Simon D. Bouton C. Reutenauer L. Hertzog A. Golik P. Procaccio V. Patel M. Drapier JC. Koenig M. Puccio H. Friedreich ataxia: the oxidative stress paradox. Hum Mol Genet. 2005;14:463–474. doi: 10.1093/hmg/ddi042. [DOI] [PubMed] [Google Scholar]

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    § V. Frataxin and Iron Homeostasis

    FRDA is most commonly (96% to 98%) caused by homozygous hyperexpansion of a GAA trinucleotide repeat in the first intron of the frataxin gene, which results in marked repression of frataxin transcription.

    “FRDA is most commonly (96% to 98%) caused by the homozygous hyperexpansion of a GAA trinucleotide repeat in the first intron of the frataxin gene, which results in a marked repression of frataxin transcription (37).”
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    • cites [37] Campuzano V. Montermini L. Molto MD. Pianese L. Cossee M. Cavalcanti F. Monros E. Rodius F. Duclos F. Monticelli A. Zara F. Canizares J. Koutnikova H. Bidichandani SI. Gellera C. Brice A. Trouillas P. De Michele G. Filla A. De Frutos R. Palau F. Patel PI. Di Donato S. Mandel JL. Cocozza S. Koenig M. Pandolfo M. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271:1423–1427. doi: 10.1126/science.271.5254.1423. [DOI] [PubMed] [Google Scholar] source

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    § V. Frataxin and Iron Homeostasis

    Skeletal muscle of FRDA patients had impaired mitochondrial respiration and a profound deficit of ATP production.

    “It was demonstrated that the skeletal muscle of FRDA patients had impaired mitochondrial respiration and a profound deficit of ATP production (189)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Lodi R. Cooper JM. Bradley JL. Manners D. Styles P. Taylor DJ. Schapira AH. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A. 1999;96:11492–11495. doi: 10.1073/pnas.96.20.11492. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    § V. Frataxin and Iron Homeostasis

    In yeast frataxin, MPP cleaves the N-terminal 20 amino acids in the first step, followed by a second cleavage that gives rise to mature yeast frataxin consisting of 123 amino acids (aa 52 to 174).

    “In yeast frataxin, the MPP cleaves the N-terminal 20 amino acids in the first step, followed by the second cleavage that gives rise to the mature yeast frataxin, consisting of 123 amino acids (aa 52 to 174) (28)”
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    • cites [28] Branda SS. Cavadini P. Adamec J. Kalousek F. Taroni F. Isaya G. Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase. J Biol Chem. 1999;274:22763–22769. doi: 10.1074/jbc.274.32.22763. [DOI] [PubMed] [Google Scholar]

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    § V. Frataxin and Iron Homeostasis

    Oligomycin-mediated oxidative stress induced superoxide dismutases and iron import in normal fibroblasts, whereas these responses were attenuated in FRDA patients' fibroblasts, suggesting that frataxin deficiency impairs an antioxidant defense mechanism.

    “Oligomycin-mediated oxidative stress induced both superoxide dismutases (SODs) and iron import in normal fibroblasts, whereas these responses were attenuated in FRDA patients' fibroblasts, suggesting that frataxin deficiency impairs an antioxidant defense mechanism (46).”
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    • cites [46] Chantrel-Groussard K. Geromel V. Puccio H. Koenig M. Munnich A. Rotig A. Rustin P. Disabled early recruitment of antioxidant defenses in Friedreich's ataxia. Hum Mol Genet. 2001;10:2061–2067. doi: 10.1093/hmg/10.19.2061. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    Mice with targeted disruption of hepatic frataxin exhibited a reduced life span and development of multiple hepatic tumor growths.

    “These mice exhibited a reduced life span and development of multiple hepatic tumor growths (289).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [289] Thierbach R. Schulz TJ. Isken F. Voigt A. Mietzner B. Drewes G. von Kleist-Retzow JC. Wiesner RJ. Magnuson MA. Puccio H. Pfeiffer AF. Steinberg P. Ristow M. Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Hum Mol Genet. 2005;14:3857–3864. doi: 10.1093/hmg/ddi410. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    Homozygous deletions in the frataxin gene in mice caused embryonic lethality, indicating an important role of frataxin in mouse development.

    “Homozygous deletions in the frataxin gene in mice caused embryonic lethality, indicating an important role of frataxin in mouse development (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Cossee M. Puccio H. Gansmuller A. Koutnikova H. Dierich A. LeMeur M. Fischbeck K. Dolle P. Koenig M. Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum Mol Genet. 2000;9:1219–1226. doi: 10.1093/hmg/9.8.1219. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    In wild-type and frataxin transgenic mice, doxorubicin challenge increased similar levels of serum creatine kinase and lactate dehydrogenase, suggesting that overexpression of frataxin did not protect from doxorubicin-induced cardiotoxicity.

    “In both wild-type and frataxin transgenic mice, 5 mg/kg of doxorubicin challenge increased similar levels of serum creatine kinase and lactate dehydrogenase, markers for heart and skeletal muscle damage, suggesting that overexpression of frataxin did not protect from doxorubicin-induced cardiotoxicity (203).”
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    • cites [203] Miranda CJ. Santos MM. Ohshima K. Tessaro M. Sequeiros J. Pandolfo M. Frataxin overexpressing mice. FEBS Lett. 2004;572:281–288. doi: 10.1016/j.febslet.2004.07.022. [DOI] [PubMed] [Google Scholar]

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    § V. Frataxin and Iron Homeostasis

    Homozygous insertion of a (GAA)230 repeat into the mouse frataxin gene or heterozygous frataxin(-)/(GAA)230 repeat showed no obvious pathologic phenotype, with normal gait and limb movement and normal serum and tissue iron levels.

    “In contrast to these observations, homozygous insertion of a (GAA)230 repeat into the mouse frataxin gene (averaging 75% of wild-type frataxin expression levels) or heterozygous frataxin(-)/(GAA)230 repeat (reduction to 25% to 36% of wild-type mice frataxin levels that are compatible with frataxin expression level in mild but clinically evident FRDA patients) showed no obvious pathologic phenotype”
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    • cites [202] Miranda CJ. Santos MM. Ohshima K. Smith J. Li L. Bunting M. Cossee M. Koenig M. Sequeiros J. Kaplan J. Pandolfo M. Frataxin knockin mouse. FEBS Lett. 2002;512:291–297. doi: 10.1016/s0014-5793(02)02251-2. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    Yeast frataxin mutations that impair ferroxidation or mineralization activity increased sensitivity to oxidative stress, suggesting a role of frataxin in iron detoxification and antioxidant defense.

    “Furthermore, yeast frataxin mutations that impair its ferroxidation or mineralization activity increased sensitivity to oxidative stress, suggesting the role of frataxin in iron detoxification and antioxidant defense (97).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Gakh O. Park S. Liu G. Macomber L. Imlay JA. Ferreira GC. Isaya G. Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. Hum Mol Genet. 2006;15:467–479. doi: 10.1093/hmg/ddi461. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    In FRDA patient lymphoblast and fibroblast cell lines, no difference was found between control and FRDA patient cells in the concentration of mitochondrial chelatable iron or TfR-mediated iron transport.

    “However, in FRDA patient lymphoblast and fibroblast cell lines, no difference was found between control and FRDA patient cells in the concentration of mitochondrial chelatable iron or TfR-mediated iron transport (283)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [283] Sturm B. Bistrich U. Schranzhofer M. Sarsero JP. Rauen U. Scheiber-Mojdehkar B. de Groot H. Ioannou P. Petrat F. Friedreich's ataxia, no changes in mitochondrial labile iron in human lymphoblasts and fibroblasts: a decrease in antioxidative capacity? J Biol Chem. 2005;280:6701–6708. doi: 10.1074/jbc.M408717200. [DOI] [PubMed] [Google Scholar]

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    § V. Frataxin and Iron Homeostasis

    Fibroblasts of FRDA patients show increased glutathionylation of total proteins, probably because of accumulation of iron and ROS.

    “As a potential pathogenesis of FRDA, increase in glutathionylation of total proteins was demonstrated in fibroblasts of FRDA patients, probably because of accumulation of iron and ROS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [236] Pastore A. Tozzi G. Gaeta LM. Bertini E. Serafini V. Di Cesare S. Bonetto V. Casoni F. Carrozzo R. Federici G. Piemonte F. Actin glutathionylation increases in fibroblasts of patients with Friedreich's ataxia: a potential role in the pathogenesis of the disease. J Biol Chem. 2003;278:42588–42595. doi: 10.1074/jbc.M301872200. [DOI] [PubMed] [Google Scholar] source

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    § V. Frataxin and Iron Homeostasis

    The GAA repeat in FRDA patients ranges from 100 to >1,000 repeats, whereas normal individuals have fewer than 35 repeats.

    “The GAA repeat in FRDA patients ranges from 100 to >1,000 repeats, whereas normal individuals have fewer than 35 repeats (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Campuzano V. Montermini L. Molto MD. Pianese L. Cossee M. Cavalcanti F. Monros E. Rodius F. Duclos F. Monticelli A. Zara F. Canizares J. Koutnikova H. Bidichandani SI. Gellera C. Brice A. Trouillas P. De Michele G. Filla A. De Frutos R. Palau F. Patel PI. Di Donato S. Mandel JL. Cocozza S. Koenig M. Pandolfo M. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271:1423–1427. doi: 10.1126/science.271.5254.1423. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    Targeted disruption of hepatic frataxin expression caused increased oxidative stress, impaired mitochondrial function of respiration and ATP synthesis, and decreased activity of ISC-containing proteins in liver.

    “Furthermore, targeted disruption of hepatic frataxin expression caused increased oxidative stress, impaired mitochondrial function of respiration and ATP synthesis, along with decreased activity of ISC-containing proteins in liver (289).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [289] Thierbach R. Schulz TJ. Isken F. Voigt A. Mietzner B. Drewes G. von Kleist-Retzow JC. Wiesner RJ. Magnuson MA. Puccio H. Pfeiffer AF. Steinberg P. Ristow M. Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Hum Mol Genet. 2005;14:3857–3864. doi: 10.1093/hmg/ddi410. [DOI] [PubMed] [Google Scholar]

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    Interpretationreasoning
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    The disease phenotype is prominent in heart tissue and nervous system, suggesting that the required amount of frataxin in each tissue may be variable.

    “The disease phenotype is prominent in the heart tissue and nervous system, suggesting that the required amount of frataxin in each tissue may be variable.”
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    § V. Frataxin and Iron Homeostasis

    Cells derived from FRDA patients contained a 40% increase in mitochondrial iron content and were more susceptible to iron-mediated cytotoxicity and hydrogen peroxide.

    “Similarly, cells derived from FRDA patients contained 40% increase in mitochondrial iron content and were more susceptible to iron-mediated cytotoxicity and hydrogen peroxide (287, 321)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [287] Tan G. Chen LS. Lonnerdal B. Gellera C. Taroni FA. Cortopassi GA. Frataxin expression rescues mitochondrial dysfunctions in FRDA cells. Hum Mol Genet. 2001;10:2099–2107. doi: 10.1093/hmg/10.19.2099. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [321] Wong A. Yang J. Cavadini P. Gellera C. Lonnerdal B. Taroni F. Cortopassi G. The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet. 1999;8:425–430. doi: 10.1093/hmg/8.3.425. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    In yeast, frataxin is involved in mitochondrial iron efflux or iron storage.

    “In yeast, it was demonstrated that frataxin is involved in mitochondrial iron efflux (252) or iron storage (96, 234).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [252] Radisky DC. Babcock MC. Kaplan J. The yeast frataxin homologue mediates mitochondrial iron efflux: evidence for a mitochondrial iron cycle. J Biol Chem. 1999;274:4497–4499. doi: 10.1074/jbc.274.8.4497. [DOI] [PubMed] [Google Scholar] source

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    • cites [96] Gakh O. Adamec J. Gacy AM. Twesten RD. Owen WG. Isaya G. Physical evidence that yeast frataxin is an iron storage protein. Biochemistry. 2002;41:6798–6804. doi: 10.1021/bi025566+. [DOI] [PubMed] [Google Scholar] source

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    • cites [234] Park S. Gakh O. O'Neill HA. Mangravita A. Nichol H. Ferreira GC. Isaya G. Yeast frataxin sequentially chaperones and stores iron by coupling protein assembly with iron oxidation. J Biol Chem. 2003;278:31340–31351. doi: 10.1074/jbc.M303158200. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    The most abundant frataxin mRNA is a transcript from exon 1 to exon 5a, with a size of 1.3 kb.

    “The most abundant frataxin mRNA is a transcript from exon 1 to exon 5a, with a size of 1.3 kb (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Campuzano V. Montermini L. Molto MD. Pianese L. Cossee M. Cavalcanti F. Monros E. Rodius F. Duclos F. Monticelli A. Zara F. Canizares J. Koutnikova H. Bidichandani SI. Gellera C. Brice A. Trouillas P. De Michele G. Filla A. De Frutos R. Palau F. Patel PI. Di Donato S. Mandel JL. Cocozza S. Koenig M. Pandolfo M. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271:1423–1427. doi: 10.1126/science.271.5254.1423. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    Frataxin interacts with aconitase in a citrate-dependent manner and protects or restores aconitase activity by converting the inactive [3Fe-4S]1+ form to the active [4Fe-4S]2+ form.

    “Frataxin was also found to interact with aconitase in a citrate-dependent manner and protects or restores the aconitase activity by converting the inactive [3Fe-4S]1+ form to the active [4Fe-4S]2+ form of aconitase (29).”
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    • cites [29] Bulteau AL. O'Neill HA. Kennedy MC. Ikeda-Saito M. Isaya G. Szweda LI. Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science. 2004;305:242–245. doi: 10.1126/science.1098991. [DOI] [PubMed] [Google Scholar]

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    Interpretationcitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    Frataxin is involved in heme synthesis and ISC formation through interactions with proteins involved in these biosynthesis pathways.

    “Growing evidence indicates that frataxin is involved in heme (ferrous-protoporphyrin IX) synthesis and ISC formation through interactions with proteins involved in these biosynthesis pathways (Table 2).”
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    • cites Table 2

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    Expression of human mitochondrial ferritin or human ferritin L-chain rescued frataxin-deficient yeast, suggesting functional homology between iron-storage protein ferritin and frataxin.

    “Interestingly, expression of human mitochondrial ferritin (ferritin H-like protein) or human ferritin L-chain rescued frataxin-deficient yeast (36, 70), suggesting functional homology between iron-storage protein ferritin and frataxin.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Campanella A. Isaya G. O'Neill HA. Santambrogio P. Cozzi A. Arosio P. Levi S. The expression of human mitochondrial ferritin rescues respiratory function in frataxin-deficient yeast. Hum Mol Genet. 2004;13:2279–2288. doi: 10.1093/hmg/ddh232. [DOI] [PubMed] [Google Scholar]

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    • cites [70] Desmyter L. Dewaele S. Reekmans R. Nystrom T. Contreras R. Chen C. Expression of the human ferritin light chain in a frataxin mutant yeast affects ageing and cell death. Exp Gerontol. 2004;39:707–715. doi: 10.1016/j.exger.2004.01.008. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    Aconitase and mitochondrial ISC respiratory complexes I, II, and III are deficient in YFH1-deleted yeast and FRDA patient cells, resulting in defects in ISC protein maturation, respiratory deficiency, and mitochondrial iron accumulation.

    “It was reported that aconitase (an ISC-containing citric cycle enzyme that converts citrate to isocitrate) and mitochondrial ISC respiratory complexes I, II, and III are deficient in YFH1-deleted yeast, as well as FRDA patient cells (261), resulting in defects in ISC protein maturation, respiratory deficiency, and mitochondrial iron accumulation (47, 209).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [261] Rotig A. de Lonlay P. Chretien D. Foury F. Koenig M. Sidi D. Munnich A. Rustin P. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997;17:215–217. doi: 10.1038/ng1097-215. [DOI] [PubMed] [Google Scholar]

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    • cites [47] Chen OS. Hemenway S. Kaplan J. Inhibition of Fe-S cluster biosynthesis decreases mitochondrial iron export: evidence that Yfh1p affects Fe-S cluster synthesis. Proc Natl Acad Sci U S A. 2002;99:12321–12326. doi: 10.1073/pnas.192449599. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [209] Muhlenhoff U. Richhardt N. Ristow M. Kispal G. Lill R. The yeast frataxin homolog Yfh1p plays a specific role in the maturation of cellular Fe/S proteins. Hum Mol Genet. 2002;11:2025–2036. doi: 10.1093/hmg/11.17.2025. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    Frataxin-deficient yeast showed more production of hydrogen peroxide, higher sensitivity to DNA-damaging agents, and increased chromosomal instability, suggesting that detoxification of mitochondrial iron is a primary function of frataxin.

    “The frataxin-deficient yeast also showed more production of hydrogen peroxide, higher sensitivity to DNA-damaging agents, and increased chromosomal instability (152), suggesting that detoxification of mitochondrial iron is a primary function of frataxin (97).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [152] Karthikeyan G. Lewis LK. Resnick MA. The mitochondrial protein frataxin prevents nuclear damage. Hum Mol Genet. 2002;11:1351–1362. doi: 10.1093/hmg/11.11.1351. [DOI] [PubMed] [Google Scholar]

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    • cites [97] Gakh O. Park S. Liu G. Macomber L. Imlay JA. Ferreira GC. Isaya G. Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. Hum Mol Genet. 2006;15:467–479. doi: 10.1093/hmg/ddi461. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    β-alanine-linked polyamides bind the GAA:TTC repeat, resulting in disruption of the sticky-DNA conformation and alleviation of transcriptional repression of the frataxin gene in the FRDA lymphoid cell line.

    “The attempt to restore frataxin expression by specifically targeting expanded GAA:TTC repeat demonstrated that β-alanine–linked polyamides bind the GAA:TTC repeat, resulting in disruption of the sticky-DNA conformation and alleviation of transcriptional repression of the frataxin gene in the FRDA lymphoid cell line (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Burnett R. Melander C. Puckett JW. Son LS. Wells RD. Dervan PB. Gottesfeld JM. DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA.TTC repeats in Friedreich's ataxia. Proc Natl Acad Sci USA. 2006;103:11497–11502. doi: 10.1073/pnas.0604939103. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    Yeast Mrs3 and Mrs4 serve as mitochondrial iron-transport proteins and cooperate with YFH1 in providing iron for heme synthesis.

    “Yeast Mrs3 and Mrs4 were shown to serve as mitochondrial iron-transport proteins (94) and to cooperate with YFH1 in providing iron for heme synthesis (335).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [94] Foury F. Roganti T. Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J Biol Chem. 2002;277:24475–24483. doi: 10.1074/jbc.M111789200. [DOI] [PubMed] [Google Scholar]

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    • cites [335] Zhang Y. Lyver ER. Knight SA. Lesuisse E. Dancis A. Frataxin and mitochondrial carrier proteins, Mrs3p and Mrs4p, cooperate in providing iron for heme synthesis. J Biol Chem. 2005;280:19794–19807. doi: 10.1074/jbc.M500397200. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    The human frataxin gene is located on chromosome 9 (q13-q21.1) and consists of seven exons spanning >95 kb of genomic DNA.

    “The human frataxin gene is located on chromosome 9 (q13-q21.1) consisting of seven exons spanning >95 kb of the genomic DNA (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Campuzano V. Montermini L. Molto MD. Pianese L. Cossee M. Cavalcanti F. Monros E. Rodius F. Duclos F. Monticelli A. Zara F. Canizares J. Koutnikova H. Bidichandani SI. Gellera C. Brice A. Trouillas P. De Michele G. Filla A. De Frutos R. Palau F. Patel PI. Di Donato S. Mandel JL. Cocozza S. Koenig M. Pandolfo M. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271:1423–1427. doi: 10.1126/science.271.5254.1423. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    The increased susceptibility of FRDA patient cells to iron-mediated cytotoxicity and hydrogen peroxide was rescued by treatment with deferoxamine or by near-physiologic levels of frataxin expression.

    “which was rescued by treatment with the iron chelator deferoxamine (321) or by near-physiologic levels of frataxin expression (287).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [321] Wong A. Yang J. Cavadini P. Gellera C. Lonnerdal B. Taroni F. Cortopassi G. The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet. 1999;8:425–430. doi: 10.1093/hmg/8.3.425. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [287] Tan G. Chen LS. Lonnerdal B. Gellera C. Taroni FA. Cortopassi GA. Frataxin expression rescues mitochondrial dysfunctions in FRDA cells. Hum Mol Genet. 2001;10:2099–2107. doi: 10.1093/hmg/10.19.2099. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    YFH1 interacts with yeast ferrochelatase (Hem15p) in vitro, and YFH1 deficiency results in a defect of iron use in ferrochelatase activity.

    “In the same study, YFH1 was shown to interact with the yeast ferrochelatase (Hem15p) in vitro, and that the YFH1 deficiency resulted in the defect of iron use in ferrochelatase activity (181).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Lesuisse E. Santos R. Matzanke BF. Knight SA. Camadro JM. Dancis A. Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1) Hum Mol Genet. 2003;12:879–889. doi: 10.1093/hmg/ddg096. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    Human mature frataxin has a compact structure with no signature of iron binding or oligomerization in the presence of iron.

    “In human mature frataxin, the structure is compact, with no signature of iron binding or oligomerization in the presence of iron (212)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [212] Musco G. Stier G. Kolmerer B. Adinolfi S. Martin S. Frenkiel T. Gibson T. Pastore A. Towards a structural understanding of Friedreich's ataxia: the solution structure of frataxin. Structure. 2000;8:695–707. doi: 10.1016/s0969-2126(00)00158-1. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    Turning off the yeast frataxin promoter in an inducible system caused accumulation of iron in mitochondria and resulted in mitochondrial and nuclear oxidative DNA damage.

    “Turning off the yeast frataxin promoter in an inducible system caused accumulation of iron in mitochondria and resulted in mitochondrial and nuclear oxidative DNA damage (153).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Karthikeyan G. Santos JH. Graziewicz MA. Copeland WC. Isaya G. Van Houten B. Resnick MA. Reduction in frataxin causes progressive accumulation of mitochondrial damage. Hum Mol Genet. 2003;12:3331–3342. doi: 10.1093/hmg/ddg349. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § V. Frataxin and Iron Homeostasis

    Mature human frataxin was reported to assemble in >600-kDa homopolymers and bind ∼10 atoms of iron per frataxin oligomer.

    “whereas the mature human frataxin was reported to assemble in >600-kDa homopolymers and bind ∼10 atoms of iron per frataxin oligomer (44).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Cavadini P. O'Neill HA. Benada O. Isaya G. Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Hum Mol Genet. 2002;11:217–227. doi: 10.1093/hmg/11.3.217. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    Type 1 HH is associated with several mutations of the HFE gene, which was originally identified during an analysis of 178 individuals with HH.

    “Type 1 HH is associated with several mutations of the HFE gene, which was originally identified during an analysis of 178 individuals with HH (82).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Feder JN. Gnirke A. Thomas W. Tsuchihashi Z. Ruddy DA. Basava A. Dormishian F. Domingo R Jr. Ellis MC. Fullan A. Hinton LM. Jones NL. Kimmel BE. Kronmal GS. Lauer P. Lee VK. Loeb DB. Mapa FA. McClelland E. Meyer NC. Mintier GA. Moeller N. Moore T. Morikang E. Prass CE. Quintana L. Starnes SM. Schatzman RC. Brunke KJ. Drayna DT. Risch NJ. Bacon BR. Wolff RK. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13:399–408. doi: 10.1038/ng0896-399. [DOI] [PubMed] [Google Scholar] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § VI. Functional Iron Overload and Human Health

    Hereditary hemochromatosis (HH) is the most common form of iron-overload disorder in individuals of northern European descent.

    “Hereditary hemochromatosis (HH) is the most common form of iron-overload disorder in individuals of northern European descent (299).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [299] Trinder D. Fox C. Vautier G. Olynyk JK. Molecular pathogenesis of iron overload. Gut. 2002;51:290–295. doi: 10.1136/gut.51.2.290. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    Individuals with juvenile hemochromatosis incur cardiomyopathies, liver cirrhosis, and diabetes, and have increased morbidity associated with decreased life expectancy because of systemic organ failure.

    “Individuals with juvenile hemochromatosis incur cardiomyopathies, liver cirrhosis, and diabetes, and have increased morbidity associated with a decreased life expectancy because of systemic organ failure (244).”
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    • cites [244] Pietrangelo A. Hereditary hemochromatosis: a new look at an old disease. N Engl J Med. 2004;350:2383–2397. doi: 10.1056/NEJMra031573. [DOI] [PubMed] [Google Scholar] source

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    § VI. Functional Iron Overload and Human Health

    HFE2 is a GPI-anchored protein that appears to be a sensor of dietary iron levels.

    “HFE2 is a GPI-anchored protein that appears to be a sensor of dietary iron levels (230).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [230] Papanikolaou G. Samuels ME. Ludwig EH. MacDonald ML. Franchini PL. Dube MP. Andres L. MacFarlane J. Sakellaropoulos N. Politou M. Nemeth E. Thompson J. Risler JK. Zaborowska C. Babakaiff R. Radomski CC. Pape TD. Davidas O. Christakis J. Brissot P. Lockitch G. Ganz T. Hayden MR. Goldberg YP. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36:77–82. doi: 10.1038/ng1274. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    In a mouse model for FRDA, the antioxidant Idebenone delayed the onset of cardiac dysfunction without improvement of deficiency in ISC proteins.

    “In a mouse model for FRDA, the antioxidant Idebenone delayed the onset of cardiac dysfunction without improvement of deficiency in ISC proteins (274).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [274] Seznec H. Simon D. Monassier L. Criqui-Filipe P. Gansmuller A. Rustin P. Koenig M. Puccio H. Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich ataxia. Hum Mol Genet. 2004;13:1017–1024. doi: 10.1093/hmg/ddh114. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    Frataxin-encoding adeno-associated virus and lentivirus vectors increased frataxin expression and decreased sensitivity to oxidant stress in primary FRDA patient fibroblasts.

    “In addition, frataxin-encoding adeno-associated virus and lentivirus vectors increased frataxin expression and decreased sensitivity to oxidant stress in primary FRDA patient fibroblasts (86).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Fleming J. Spinoulas A. Zheng M. Cunningham SC. Ginn SL. McQuilty RC. Rowe PB. Alexander IE. Partial correction of sensitivity to oxidant stress in Friedreich ataxia patient fibroblasts by frataxin-encoding adeno-associated virus and lentivirus vectors. Hum Gene Ther. 2005;16:947–956. doi: 10.1089/hum.2005.16.947. [DOI] [PubMed] [Google Scholar]

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    § VI. Functional Iron Overload and Human Health

    Normal HFE protein associates with TfR, usually in conjunction with β2-microglobulin, and competes with Tf for TfR binding, thereby inhibiting Fe-Tf uptake via the TfR in cells.

    “Normal HFE protein associates with TfR, usually in conjunction with β2-microglobulin, and competes with Tf for TfR binding, thereby inhibiting Fe-Tf uptake via the TfR in cells (83, 179).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] Feder JN. Penny DM. Irrinki A. Lee VK. Lebron JA. Watson N. Tsuchihashi Z. Sigal E. Bjorkman PJ. Schatzman RC. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A. 1998;95:1472–1477. doi: 10.1073/pnas.95.4.1472. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    • cites [179] Lebron JA. West AP Jr. Bjorkman PJ. The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J Mol Biol. 1999;294:239–245. doi: 10.1006/jmbi.1999.3252. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    In mice, HFE2 is localized to the surface of periportal hepatocytes, and HFE2-mutant mice display iron loading and a striking decrease in hepcidin upregulation in response to increased iron from exogenous sources.

    “In mice, HFE2 is localized to the surface of periportal hepatocytes, and HFE2-mutant mice display iron loading and a striking decrease in hepcidin upregulation in response to increased iron from exogenous sources, compared with controls (217).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [217] Niederkofler V. Salie R. Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest. 2005;115:2180–2186. doi: 10.1172/JCI25683. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    § VI. Functional Iron Overload and Human Health

    Mutation of HFE2 appears to impede normal iron sensing, thus possibly allowing increased iron uptake through decreased expression of hepcidin, the negative regulator of Fpn.

    “Thus, mutation of HFE2 appears to impede normal iron sensing, thus possibly allowing increased iron uptake through decreased expression of hepcidin, the negative regulator of Fpn.”
    Quote in the paperSubstantial claim

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    § VI. Functional Iron Overload and Human Health

    The C282Y HFE mutant is retained in the ER and Golgi and is rapidly degraded.

    “Further studies demonstrated that the C282Y HFE mutant is retained in the ER and Golgi and is rapidly degraded (316).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [316] Waheed A. Parkkila S. Zhou XY. Tomatsu S. Tsuchihashi Z. Feder JN. Schatzman RC. Britton RS. Bacon BR. Sly WS. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci U S A. 1997;94:12384–12389. doi: 10.1073/pnas.94.23.12384. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    Resulting iron overload leads to structural damage from physical iron accumulation and oxidative damage to tissue, protein, lipids, and DNA resulting from iron-induced oxidative stress.

    “Resulting iron overload leads to a number of different pathologies, including structural damage from physical iron accumulation and oxidative damage to tissue, protein, lipids, and DNA resulting from iron-induced oxidative stress (229).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Papanikolaou G. Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol. 2005;202:199–211. doi: 10.1016/j.taap.2004.06.021. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Frataxin, heme synthesis, and iron–sulfur cluster biogenesis

    HIF-2α knockout mice have impaired mitochondrial respiration, sensitized mitochondrial permeability transition pore opening, and reduced activity of aconitase, because of marked reduction of frataxin mRNA expression in HIF-2α−/− livers.

    “Recently, HIF-2α knockout mice were shown to have impaired mitochondrial respiration, sensitized mitochondrial permeability transition pore opening, and reduced activity of aconitase, because of marked reduction of frataxin mRNA expression in HIF-2α−/−livers (224).”
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    • cites [224] Oktay Y. Dioum E. Matsuzaki S. Ding K. Yan LJ. Haller RG. Szweda LI. Garcia JA. Hypoxia-inducible factor 2alpha regulates expression of the mitochondrial aconitase chaperone protein frataxin. J Biol Chem. 2007;282:11750–11756. doi: 10.1074/jbc.M611133200. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    The H63D mutation in HFE is commonly observed but does not lead to the same HH phenotype, probably because it is processed and expressed in the same manner as wild-type HFE.

    “Another mutation (H63D) in HFE is commonly observed, but does not lead to the same HH phenotype, probably because it is processed and expressed in the same manner as wild-type HFE (316).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [316] Waheed A. Parkkila S. Zhou XY. Tomatsu S. Tsuchihashi Z. Feder JN. Schatzman RC. Britton RS. Bacon BR. Sly WS. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci U S A. 1997;94:12384–12389. doi: 10.1073/pnas.94.23.12384. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    The C282Y mutation disrupts the formation of the disulfide bridge necessary for proper protein formation, causing the aberrant protein to remain in the Golgi.

    “This mutation disrupts the formation of the disulfide bridge, which appears to be necessary for proper protein formation, causing the aberrant protein remains in the Golgi (24, 83).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Bjorkman PJ. Parham P. Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem. 1990;59:253–288. doi: 10.1146/annurev.bi.59.070190.001345. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [83] Feder JN. Penny DM. Irrinki A. Lee VK. Lebron JA. Watson N. Tsuchihashi Z. Sigal E. Bjorkman PJ. Schatzman RC. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A. 1998;95:1472–1477. doi: 10.1073/pnas.95.4.1472. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    Studies of several mutant isoforms of HFE2 in HeLa and HepG2 cells revealed that several of the mutations resulted in the loss of the GPI anchor and were primarily retained in the ER or secreted as soluble protein.

    “Studies of several mutant isoforms of HFE2 in HeLa and HepG2 cells revealed that several of the mutations resulted in the loss of the GPI anchor and were primarily retained in the ER or secreted as soluble protein (278).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [278] Silvestri L. Pagani A. Fazi C. Gerardi G. Levi S. Arosio P. Camaschella C. Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis. Blood. 2007;109:4503–4510. doi: 10.1182/blood-2006-08-041004. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    HH is classified on a genetic, biochemical, and clinical basis as types 1 through 4, with phenotype/clinical outcomes used to determine the type.

    “HH is classified on a genetic, biochemical, and clinical basis as types 1 through 4. The phenotype/clinical outcomes are used to determine the type (1 to 4) of hemochromatosis (210).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [210] Muir WA. McLaren GD. Braun W. Askari A. Evidence for heterogeneity in hereditary hemochromatosis: evaluation of 174 persons in nine families. Am J Med. 1984;76:806–814. doi: 10.1016/0002-9343(84)90991-4. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    Initially, the deleterious effects of iron loading are not clinically significant and manifest as discomfort in hand joints, increased skin pigmentation, and fatigue.

    “Initially, the deleterious effects of iron loading are not clinically significant, and manifest as discomfort in hand joints, increased skin pigmentation, and fatigue (16).”
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    • cites [16] Barton JC. Bertoli LF. Hemochromatosis: the genetic disorder of the twenty-first century. Nat Med. 1996;2:394–395. doi: 10.1038/nm0496-394. [DOI] [PubMed] [Google Scholar]

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    § VI. Functional Iron Overload and Human Health

    These outcomes resulting from aberrant iron regulation indicate that either iron accumulation or oxidative damage may be involved in damage to sensitive systems such as the eye.

    “These outcomes resulting from aberrant iron regulation indicate that either iron accumulation or oxidative damage may be involved in damage to sensitive systems such as the eye.”
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    § C. Iron regulation and neurodegeneration

    Iron deficiency may have deleterious effects on neurotransmission, myelination, and dopamine receptor and transporter functions.

    “Iron deficiency may have deleterious effects on neurotransmission, myelination, and dopamine receptor and transporter functions (18).”
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    • cites [18] Beard J. Iron deficiency alters brain development and functioning. J Nutr. 2003;133:1468S–1472S. doi: 10.1093/jn/133.5.1468S. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    Type 3 HH is pathophysiologically similar to type 1 but occurs as a result of a mutation in TfR2.

    “Type 3 HH is pathophysiologically similar to type 1; however, it occurs as a result of a mutation in TfR2 (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Camaschella C. Roetto A. Cali A. De Gobbi M. Garozzo G. Carella M. Majorano N. Totaro A. Gasparini P. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14–15. doi: 10.1038/75534. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Iron regulation and neurodegeneration

    Individuals with PD typically have bradykinesias, dyskinesias, resting tremors, loss of reflexes, and inability to initiate movement, which are ameliorated by the administration of the dopamine precursor, levodopa.

    “Individuals with PD typically have bradykinesias, dyskinesias, resting tremors, loss of reflexes, and inability to initiate movement, which are ameliorated by the administration of the dopamine precursor, levodopa (79).”
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    • cites [79] Fahn S. Description of Parkinson's disease as a clinical syndrome. Ann N Y Acad Sci. 2003;991:1–14. doi: 10.1111/j.1749-6632.2003.tb07458.x. [DOI] [PubMed] [Google Scholar] source

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    § C. Iron regulation and neurodegeneration

    Monkeys exhibited age-related declines in motor function and dopamine release in the striatum, whereas iron concentration in the striatum increased.

    “Monkeys exhibited age-related declines in motor function and dopamine release in the striatum, whereas iron concentration in the striatum increased.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Cass WA. Grondin R. Andersen AH. Zhang Z. Hardy PA. Hussey-Andersen LK. Rayens WS. Gerhardt GA. Gash DM. Iron accumulation in the striatum predicts aging-related decline in motor function in rhesus monkeys. Neurobiol Aging. 2007;28:258–271. doi: 10.1016/j.neurobiolaging.2005.12.010. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    A mouse model of type 3 HH with a premature stop codon (Y245X) in TfR2 showed aberrant iron homeostasis, including early hepatocellular iron overload coupled with decreased splenic iron and elevated transferrin saturation.

    “In a study of a mouse model of type 3 HH, a premature stop codon (Y245X) was introduced in TfR2 to create an orthologous mutation to the Y250X observed in some individuals with type 3 HH (89). The resulting mutant mice showed aberrant iron homeostasis, including early hepatocellular iron overload coupled with decreased splenic iron and elevated transferrin saturation (89).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Fleming RE. Ahmann JR. Migas MC. Waheed A. Koeffler HP. Kawabata H. Britton RS. Bacon BR. Sly WS. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc Natl Acad Sci U S A. 2002;99:10653–10658. doi: 10.1073/pnas.162360699. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Interpretationcitation
    § VI. Functional Iron Overload and Human Health

    TfR2 is important in iron homeostasis, and its absence leads to clinically significant disruption of iron homeostasis.

    “Thus, TfR2 is important in iron homeostasis, and its absence leads to clinically significant disruption of iron homeostasis.”
    Quote in the paperSubstantial claim

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    § VI. Functional Iron Overload and Human Health

    TfR2 does not associate with HFE, suggesting an alternative role for TfR2 mutation in HH.

    “Studies have shown that TfR2 does not associate with HFE, suggesting an alternative role for TfR2 mutation in HH (320).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [320] West AP Jr. Bennett MJ. Sellers VM. Andrews NC. Enns CA. Bjorkman PJ. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. J Biol Chem. 2000;275:38135–38138. doi: 10.1074/jbc.C000664200. [DOI] [PubMed] [Google Scholar]

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    Iron accumulation in the liver in type 1 HH results in the downregulation of TfR1, but TfR2 is continually expressed even during HH-mediated iron loading.

    “Interestingly, iron accumulation in the liver in type 1 HH results in the downregulation of TfR1, but in the case of TfR2, it is continually expressed even during HH-mediated iron loading (90).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Fleming RE. Migas MC. Holden CC. Waheed A. Britton RS. Tomatsu S. Bacon BR. Sly WS. Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc Natl Acad Sci U S A. 2000;97:2214–2219. doi: 10.1073/pnas.040548097. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    TfR2 does not appear to be regulated by iron concentrations, for it lacks IRE in its mRNA and is not inducible by iron deficiency.

    “In addition, TfR2 does not appear to be regulated by iron concentrations, for it lacks IRE in its mRNA and is not inducible by iron deficiency (90).”
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    • cites [90] Fleming RE. Migas MC. Holden CC. Waheed A. Britton RS. Tomatsu S. Bacon BR. Sly WS. Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc Natl Acad Sci U S A. 2000;97:2214–2219. doi: 10.1073/pnas.040548097. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § VI. Functional Iron Overload and Human Health

    Type 4 HH is autosomal dominant in nature, and various missense mutations lead to altered Fpn.

    “This form of HH is autosomal dominant in nature, and various missense mutations lead to altered Fpn (92, 205, 218).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [92] Fleming RE. Sly WS. Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding. J Clin Invest. 2001;108:521–522. doi: 10.1172/JCI13739. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [205] Montosi G. Donovan A. Totaro A. Garuti C. Pignatti E. Cassanelli S. Trenor CC. Gasparini P. Andrews NC. Pietrangelo A. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108:619–623. doi: 10.1172/JCI13468. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    • cites [218] Njajou OT. Vaessen N. Joosse M. Berghuis B. van Dongen JW. Breuning MH. Snijders PJ. Rutten WP. Sandkuijl LA. Oostra BA. van Duijn CM. Heutink P. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001;28:213–214. doi: 10.1038/90038. [DOI] [PubMed] [Google Scholar] source

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    § C. Iron regulation and neurodegeneration

    The D544E Cp is expressed at lower levels and exhibits decreased ferroxidase activity.

    “The D544E Cp was expressed at lower levels and exhibited decreased ferroxidase activity (135).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Hochstrasser H. Tomiuk J. Walter U. Behnke S. Spiegel J. Kruger R. Becker G. Riess O. Berg D. Functional relevance of ceruloplasmin mutations in Parkinson's disease. FASEB J. 2005;19:1851–1853. doi: 10.1096/fj.04-3486fje. [DOI] [PubMed] [Google Scholar] source

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    Interpretationcitation
    § C. Iron regulation and neurodegeneration

    Increased ferritin may not necessarily be cytoprotective and may play a role in neurodegeneration.

    “Prolonged elevation of ferritin levels in dopaminergic neurons of the midbrain resulted in a progressive age-related neurodegeneration of these cells, suggesting that increased ferritin may not necessarily be cytoprotective and may play a role in neurodegeneration (158).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Kaur D. Rajagopalan S. Chinta S. Kumar J. Di Monte D. Cherny RA. Andersen JK. Chronic ferritin expression within murine dopaminergic midbrain neurons results in a progressive age-related neurodegeneration. Brain Res. 2007;1140:188–194. doi: 10.1016/j.brainres.2006.03.006. [DOI] [PubMed] [Google Scholar] source

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    Interpretationcitation
    § C. Iron regulation and neurodegeneration

    Aberrant release of ferritin iron may lead to production of ROS and may serve as a mechanism by which altered iron management leads to cellular damage.

    “Aberrant release of ferritin iron may lead to the production of ROS and may thereby serve as a mechanism by which altered iron management may lead to cellular damage.”
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    • cites [64] De Domenico I. Vaughn MB. Li L. Bagley D. Musci G. Ward DM. Kaplan J. Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome. EMBO J. 2006;25:5396–5404. doi: 10.1038/sj.emboj.7601409. [DOI] [PMC free article] [PubMed] [Google Scholar]

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    Premisecitation
    § C. Iron regulation and neurodegeneration

    IRP1-knockout mice misregulate iron in brown fat and kidney, whereas IRP2-knockout mice exhibit aberrant management of iron in multiple tissues.

    “IRP1-knockout mice misregulate iron in specific tissues, namely in brown fat and kidney, whereas IRP2-knockout mice exhibit aberrant management of iron in multiple tissues.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Meyron-Holtz EG. Ghosh MC. Iwai K. LaVaute T. Brazzolotto X. Berger UV. Land W. Ollivierre-Wilson H. Grinberg A. Love P. Rouault TA. Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J. 2004;23:386–395. doi: 10.1038/sj.emboj.7600041. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Iron regulation and neurodegeneration

    The I63T mutant Cp isoform is expressed at half the normal level and displays a distinct decrease in ferroxidase activity in vivo.

    “In further investigation, the I63T mutant Cp isoform was expressed at half the normal level and displayed a distinct decrease in ferroxidase activity in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Hochstrasser H. Tomiuk J. Walter U. Behnke S. Spiegel J. Kruger R. Becker G. Riess O. Berg D. Functional relevance of ceruloplasmin mutations in Parkinson's disease. FASEB J. 2005;19:1851–1853. doi: 10.1096/fj.04-3486fje. [DOI] [PubMed] [Google Scholar] source

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    Premisecitation
    § C. Iron regulation and neurodegeneration

    In AD, IRP2 is localized in regions with redox active iron and is associated with neurofibrillary tangles and senile plaques.

    “In AD, IRP2 was localized in regions with redox active iron and was associated with such pathologic features as neurofibrillary tangles and senile plaques (280).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [280] Smith MA. Wehr K. Harris PL. Siedlak SL. Connor JR. Perry G. Abnormal localization of iron regulatory protein in Alzheimer's disease. Brain Res. 1998;788:232–236. doi: 10.1016/s0006-8993(98)00002-x. [DOI] [PubMed] [Google Scholar]

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    § C. Iron regulation and neurodegeneration

    In AD brain tissue, IRP1 expression is similar to controls, whereas IRP2 expression is altered.

    “A study of brain tissue from control and AD-afflicted subjects demonstrated that IRP1 expression was similar in both groups, whereas IRP2 expression was altered in AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [280] Smith MA. Wehr K. Harris PL. Siedlak SL. Connor JR. Perry G. Abnormal localization of iron regulatory protein in Alzheimer's disease. Brain Res. 1998;788:232–236. doi: 10.1016/s0006-8993(98)00002-x. [DOI] [PubMed] [Google Scholar]

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    Interpretationreasoning
    § C. Iron regulation and neurodegeneration

    Decreased expression of Cp and deficient ferroxidase activity may result in free iron accumulation and decreased antioxidant potential.

    “Decreased expression of Cp and deficient ferroxidase activity may result in “free iron” accumulation and decreased antioxidant potential.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Hochstrasser H. Tomiuk J. Walter U. Behnke S. Spiegel J. Kruger R. Becker G. Riess O. Berg D. Functional relevance of ceruloplasmin mutations in Parkinson's disease. FASEB J. 2005;19:1851–1853. doi: 10.1096/fj.04-3486fje. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    Fpn expression results in cytoplasmic iron exportation, iron release from ferritin, and subsequent ubiquitination of ferritin, targeting it for degradation by the proteasome.

    “Interestingly, Fpn expression was recently shown to result in cytoplasmic iron exportation, iron release from ferritin, and subsequent ubiquitination of ferritin, targeting it for degradation by the proteasome (64).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] De Domenico I. Vaughn MB. Li L. Bagley D. Musci G. Ward DM. Kaplan J. Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome. EMBO J. 2006;25:5396–5404. doi: 10.1038/sj.emboj.7601409. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    IRP2 is sensitive to iron levels, whereas IRP1 is not.

    “IRP2 was also sensitive to iron levels, whereas IRP1 was not, suggesting that IRP2 is the predominant posttranscriptional regulator of key genes involved iron homeostasis (200).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Meyron-Holtz EG. Ghosh MC. Iwai K. LaVaute T. Brazzolotto X. Berger UV. Land W. Ollivierre-Wilson H. Grinberg A. Love P. Rouault TA. Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J. 2004;23:386–395. doi: 10.1038/sj.emboj.7600041. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    In a study of 176 individuals with PD and 180 control subjects, five unique missense variations in the Cp gene were identified, including I63T, D554E, and R793H.

    “In this study, five unique missense variations were identified including, a single incidence of I63T, D554E, which correlated with PD and positive ultrasound for increased substantia nigra iron levels, and R793H, which was linked to increased levels of iron levels in individuals with PD and their age/ethnic-matched individuals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Hochstrasser H. Bauer P. Walter U. Behnke S. Spiegel J. Csoti I. Zeiler B. Bornemann A. Pahnke J. Becker G. Riess O. Berg D. Ceruloplasmin gene variations and substantia nigra hyperechogenicity in Parkinson disease. Neurology. 2004;63:1912–1917. doi: 10.1212/01.wnl.0000144276.29988.c3. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    Through an IRP1-dependent mechanism, MPTP administration causes upregulation of TfR, which precedes increased iron and oxidative stress.

    “Through an IRP1-dependent mechanism, MPTP administration caused upregulation of TfR, which preceded increased iron and oxidative stress (276).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [276] Shang T. Kotamraju S. Kalivendi SV. Hillard CJ. Kalyanaraman B. 1-Methyl-4-phenylpyridinium-induced apoptosis in cerebellar granule neurons is mediated by transferrin receptor iron-dependent depletion of tetrahydrobiopterin and neuronal nitric-oxide synthase-derived superoxide. J Biol Chem. 2004;279:19099–19112. doi: 10.1074/jbc.M400101200. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § VII. Conclusions and Future Directions

    Dysregulation of iron metabolism causes numerous health problems including inflammatory, metabolic, hematologic, and neurodegenerative diseases.

    “Dysregulation of iron metabolism causes numerous health problems including inflammatory, metabolic, hematologic, and neurodegenerative diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    This IRE is functional, as demonstrated by specific binding to IRP that is destroyed by functional mutation, and decreased translation in response to intracellular iron chelation.

    “This IRE was functional, as demonstrated by specific binding to IRP that was destroyed by functional mutation, and decreased translation in response to intracellular iron chelation (260).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [260] Rogers JT. Randall JD. Cahill CM. Eder PS. Huang X. Gunshin H. Leiter L. McPhee J. Sarang SS. Utsuki T. Greig NH. Lahiri DK. Tanzi RE. Bush AI. Giordano T. Gullans SR. An iron-responsive element type II in the 5′-untranslated region of the Alzheimer's amyloid precursor protein transcript. J Biol Chem. 2002;277:45518–45528. doi: 10.1074/jbc.M207435200. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    Absence of serum Cp results in low serum iron concentrations, anemia, and increased serum ferritin levels, whereas tissues, especially the retina and basal ganglia, exhibit iron overload.

    “The absence of serum Cp results in low serum iron concentrations, anemia, and increased serum ferritin levels, whereas tissues, especially the retina and the basal ganglia, exhibit iron overload.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [326] Xu X. Pin S. Gathinji M. Fuchs R. Harris ZL. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Ann N Y Acad Sci. 2004;1012:299–305. doi: 10.1196/annals.1306.024. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    Total absence of Cp results in the autosomal-recessive disorder aceruloplasminemia, in which afflicted individuals have adult-onset neurodegeneration.

    “The total absence of Cp results in an autosomal-recessive disorder, aceruloplasminemia, in which afflicted individuals have adult-onset neurodegeneration (124).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Harris ZL. Takahashi Y. Miyajima H. Serizawa M. MacGillivray RT. Gitlin JD. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci U S A. 1995;92:2539–2543. doi: 10.1073/pnas.92.7.2539. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    Recombinant mutant ferritin L can assemble into 24-subunit ferritin shells, but efficiency of assembly and capacity to incorporate iron are decreased in vitro.

    “Studies with recombinant mutant ferritin L showed that, although it was able to assemble into 24-subunit ferritin shells, the efficiency of assembly and capacity to incorporate iron were both decreased in vitro (61).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Cozzi A. Santambrogio P. Corsi B. Campanella A. Arosio P. Levi S. Characterization of the l-ferritin variant 460InsA responsible of a hereditary ferritinopathy disorder. Neurobiol Dis. 2006;23:644–652. doi: 10.1016/j.nbd.2006.05.004. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    In the CNS, Cp is found in its GPI-anchored form on cellular membranes where it is associated with Fpn.

    “In the CNS, Cp is found in its GPI-anchored form on cellular membranes where it is associated with Fpn (65).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] De Domenico I. Ward DM. di Patti MC. Jeong SY. David S. Musci G. Kaplan J. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 2007;26:2823–2831. doi: 10.1038/sj.emboj.7601735. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    A one-nucleotide insertion of adenine at position 460-461 in the ferritin L gene alters the last 20 amino acids of the C-terminal and is associated with development of a dominant adult-onset basal ganglia disease with symptoms similar to HD or parkinsonism.

    “Linkage studies identified a one-nucleotide insertion of adenine at position 460–461, which alters the last 20 amino acids of the C-terminal of ferritin L associated with the development of a dominant adult-onset basal ganglia disease with symptoms similar to those of Huntington disease (HD) or parkinsonism (50).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Chinnery PF. Crompton DE. Birchall D. Jackson MJ. Coulthard A. Lombes A. Quinn N. Wills A. Fletcher N. Mottershead JP. Cooper P. Kellett M. Bates D. Burn J. Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain. 2007;130:110–119. doi: 10.1093/brain/awl319. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    Cp-knockout mice exhibit severe defects in iron egress from astrocytes, probably resulting from lack of ferroxidase activity, which is necessary for exporter function and stability of Fpn.

    “Cp-knockout mice exhibit severe defects in iron egress from astrocytes, probably resulting from the lack of ferroxidase activity, which is necessary for the exporter function and stability of Fpn.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [148] Jeong SY. David S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem. 2003;278:27144–27148. doi: 10.1074/jbc.M301988200. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § C. Iron regulation and neurodegeneration

    Cp has a role in the regulation of cellular iron efflux and resistance to oxidative stress, and is implicated in the pathogenesis of neurodegeneration involving increased iron and oxidative damage, such as PD and AD.

    “Taken together, these results suggest a role for Cp in the regulation of cellular iron efflux and resistance to oxidative stress, and implicate Cp in the pathogenesis of neurodegeneration involving increased iron and oxidative damage, such as PD and AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cp is similar to ferritin H in having ferroxidase activity and may serve an antioxidant role in addition to its role in iron regulation.

  • May combine two claims.

    Premisecitation
    § C. Iron regulation and neurodegeneration

    Mutations in aceruloplasminemia are nonsense mutations that result in early termination of translation, causing serum Cp deficiency.

    “Mutations identified in aceruloplasminemia are nonsense mutations that result in the early termination of translation, causing serum Cp deficiency.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Harris ZL. Takahashi Y. Miyajima H. Serizawa M. MacGillivray RT. Gitlin JD. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci U S A. 1995;92:2539–2543. doi: 10.1073/pnas.92.7.2539. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § C. Iron regulation and neurodegeneration

    Absence of ferroxidase may lead to higher levels of Fe2+, which has an increased propensity to react and form ROS.

    “In addition, the absence of ferroxidase may lead to higher levels of Fe2+, which has an increased propensity to react and form ROS.”
    Quote in the paperSubstantial claim
167 of 167

  • The paper relies on this without support.

    Each day approximately 25 mg of iron is needed for erythropoiesis and other vital functions, while only 1 to 2 mg comes from intestinal iron sources.

    “Each day ∼ 25 mg of iron is needed for erythropoiesis and other vital functions. Only 1 to 2 mg of iron comes from intestinal iron sources”

  • The paper relies on this without support.

    Most cytoplasmic iron is in its reduced (ferrous) form.

    “Most cytoplasmic iron is in its reduced form, meaning that it is an excellent substrate for oxidation.”

  • The paper relies on this without support.

    Tf and TfR are absent from enterocytes.

    “Because Tf and TfR are absent from enterocytes, Tf binds iron and plays an essential role in the transport of iron only once it is exported from duodenal enterocytes into the bloodstream.”

  • The paper relies on this without support.

    Nonheme iron is predominantly insoluble Fe3+ and must be reduced before transport by DMT1.

    “It is important to note that nonheme iron is predominantly insoluble Fe3+. It must be reduced before transport by DMT1.”

  • The paper relies on this without support.

    Fpn is the only known iron exporter to date.

    “The transmembrane protein ferroportin (Fpn) is the only known iron exporter to date”

  • The paper relies on this without support.

    Iron must be oxidized to be incorporated into transferrin.

    “Because Fpn transports Fe2+ into the plasma, and iron must be oxidized to be incorporated into transferrin (Tf), it is believed that Fpn cooperates with proteins that act as ferroxidases.”

  • The paper relies on this without support.

    Ferritin is the major iron-storage protein at the cellular and organismal level.

    “Ferritin is the major iron-storage protein at the cellular and organismal level.”

  • The paper relies on this without support.

    Ferritin is responsible for the sequestration of potentially harmful, reactive iron.

    “It is responsible for the sequestration of potentially harmful, reactive iron.”

  • The paper relies on this without support.

    Ferritin stores iron in its unreactive Fe3+ form inside its shell as a result of a strong equilibrium between ferritin-bound iron (Fe3+) and the labile iron pool in the cells (Fe2+), preventing ROS formation via the Fenton reaction.

    “Ferritin stores iron in its unreactive Fe3+ form inside its shell as a result of a strong equilibrium between ferritin-bound iron (Fe3+) and the labile iron pool in the cells (Fe2+), by which ferritin prevents the formation of ROS mediated by Fenton reaction.”

  • The paper relies on this without support.

    Ferritin is ubiquitous in tissues, serum, and other multiple locations within the cell.

    “Because of its important function in the storage of iron, ferritin is ubiquitous in tissues, serum, and in other multiple locations within the cell.”

  • The paper relies on this without support.

    Ferritin is regulated at the transcriptional and posttranscriptional level by various pathways in response to diverse stimuli.

    “It is regulated at the transcriptional and posttranscriptional level by various pathways in response to diverse stimuli.”

  • The paper relies on this without support.

    In vertebrates, cytoplasmic ferritin is expressed in almost all tissues.

    “In vertebrates, cytoplasmic ferritin is expressed in almost all tissues.”

  • The paper relies on this without support.

    Proteasomal degradation commonly requires the attachment of polyubiquitin to a target protein that is misfolded.

    “Proteasomal degradation commonly requires the attachment of polyubiquitin to a target protein that is misfolded, in most cases.”

  • The paper relies on this without support.

    Polyubiquitination of ferritin protein has not been reported.

    “However, polyubiquitination of ferritin protein has not been reported.”

  • The paper relies on this without support.

    Both IRP1 and IRP2 are expressed ubiquitously in most tissues.

    “Both IRP1 and IRP2 are expressed ubiquitously in most tissues.”

  • The paper relies on this without support.

    Corneal epithelial cells are constantly exposed to UV that may cause DNA damage.

    “Corneal epithelial cells are constantly exposed to UV that may cause DNA damage.”

  • The paper relies on this without support.

    Ferritin does not possess a nuclear localization signal.

    “ferritin does not possess a nuclear localization signal”

  • The paper relies on this without support.

    Increased iron content in afflicted regions in PD and evidence of oxidative stress are present.

    “The iron-storage protein, ferritin, has been studied in PD because of the increased iron content in the afflicted regions in PD and the increase in evidence of oxidative stress.”

  • The paper relies on this without support.

    Aggregation of α-synuclein is a hallmark of PD.

    “Another hallmark of PD is the aggregation of the protein α-synuclein.”

  • The paper relies on this without support.

    An antibody for TfR that blocks iron uptake abrogates up-regulation of α-synuclein after MPP+ treatment.

    “An antibody for the TfR, which blocked iron uptake, abrogated up-regulation of α-synuclein after MPP+ treatment.”

  • The paper relies on this without support.

    Cp is similar to ferritin H in having ferroxidase activity and may serve an antioxidant role in addition to its role in iron regulation.

    “Cp is similar to ferritin H in that it also has ferroxidase activity and thereby may serve an antioxidant role in addition to its role in iron regulation.”
21 of 21

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Under high supplemental iron conditions, iron levels may exceed the binding capacity of transferrin, giving rise to non-transferrin bound iron; NTBI is taken up by liver and contributes to iron loading and hemochromatosis.

    “Under such circumstances, iron levels may exceed the binding capacity of Tf, giving rise to non-transferrin bound iron (NTB1).NTB1 is taken up by liver and has been shown to contribute to iron loading and hemochromatosis (Mackenzie et al., 2008).”

    From Iron, Oxidative Stress and Health (2012) · cites this paper as Mackenzie et al., 2008

    Section II.G says iron exceeding transferrin’s binding capacity may produce NTBI, which appears to be absorbed primarily by the liver and may contribute to cellular iron loading. It does not tie this sequence specifically to iron supplementation or say NTBI causes hemochromatosis; Section VI.A describes hereditary hemochromatosis as a genetically caused disorder in which NTBI may be present. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • When iron concentration is high, IRPs are inactivated, resulting in degradation of TfR1 mRNA while translation of ferritin mRNA occurs, minimizing iron uptake and promoting storage.

    “Conversely, when iron concentration is high, IRPs are inactivated resulting in degradation of TfR1 mRNA while translation of ferritin mRNA occurs.Thus when iron levels exceed the cellular needs, the IRE/IRP switch minimizes iron uptake and promotes iron storage”

    From Iron, Oxidative Stress and Health (2012) · cites this paper as Mackenzie, Iwasaki and Tsuji, 2008

  • When iron is depleted, IRE-IRP interaction at the 3' UTR of TfR1 stabilizes mRNA and blocks ferritin mRNA translation, upregulating TfR1 and inhibiting ferritin synthesis.

    “When iron is depleted, IRE-IRP interaction at the 3 ' UTR of TfR1 stabilizes mRNA, while imposing a steric blockade to ferritin mRNA translation.As a result, TfR1 is upregulated and stimulates acquisition of iron from plasma Tf to counteract low iron levels.Simultaneously ferritin synthesis is inhibited as storage of iron is not needed.”

    From Iron, Oxidative Stress and Health (2012) · cites this paper as Mackenzie, Iwasaki and Tsuji, 2008

  • Labile iron pool is biologically active in intracellular metabolism but toxic if present in excess; maintenance of appropriate LIP levels is critical for homeostasis.

    “LIP is biologically active in intracellular metabolism but toxic if present in excess.Maintenance of appropriate LIP levels is critical for homeostasis (Mackenzie, Iwasaki and Tsuji, 2008).”

    From Iron, Oxidative Stress and Health (2012) · cites this paper as Mackenzie, Iwasaki and Tsuji, 2008

  • Aberrant release of ferritin iron may lead to production of ROS.

    “Aberrant release of ferritin iron may lead to production of ROS (Mackenzie et al., 2008).”

    From Iron, Oxidative Stress and Health (2012) · cites this paper as Mackenzie et al., 2008

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Ceruloplasmin-knockout iron export is described in opposite terms

    Minor

    Table 4 lists accelerated iron export for Cp-knockout mice, whereas the text attributes their iron accumulation to impaired iron efflux.

  • Ceruloplasmin variant is named D554E and D544E

    Minor

    The discussion first identifies the PD-associated ceruloplasmin variant as D554E, then calls it D544E when describing its expression and activity.

  • Transferrin receptors are both absent and present in enterocytes

    Minor

    The paper says transferrin receptors are absent from enterocytes, but later says TfR2 is expressed in intestinal iron-absorbing cells.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 8

  1. Arosio P, 1976, Cancer Res, 36, 1735
  2. 1987, J Lab Clin Med, 110, 690
  3. Carella M, 1997, Am J Hum Genet, 60, 828
  4. De Domenico I, 2006, Haematologica, 91, 92
  5. Gray CP, 2003, Clin Cancer Res, 9, 2551
  6. Ponka P, 1998, Semin Hematol, 35, 35
  7. 10.1172/jci200421146 · DOI
  8. Thimmulappa RK, 2002, Cancer Res, 62, 5196

Cited by

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Related

Authors
Mackenzie, E. L., Iwasaki, K., & Tsuji, Y.
Affiliations
North Carolina State University (US)
ORCID
Venue
Antioxidants & Redox Signaling
Publisher
SAGE Publications
Published
2008-06
Volume
10
Issue
6
Pages
997-1030
ISSN
  • 1523-0864 (ISSN-L)
  • 1557-7716
DOI
10.1089/ars.2007.1893
PMC
PMC2932529
OpenAlex
W2063804160
Semantic Scholar
30be5cc97caac713f62ffa4010e5df065bdd4cfb
Cited by
526
References
351
Citations by year
2026: 16 · 2025: 47 · 2024: 43 · 2023: 44 · 2022: 41 · 2021: 38 · 2020: 36 · 2019: 28 · 2018: 23 · 2017: 23 · 2016: 21 · 2015: 17 · 2014: 29 · 2013: 16 · 2012: 27
FWCI
3.37
Type
journal article
Language
en
Open access
Locations
  • Antioxidants and Redox Signaling (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK60007, R01DK060007)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords
iron homeostasis, labile iron, iron transport, iron storage, ferroportin, hepcidin, ferritin, frataxin, oxidative stress, iron overload, hemochromatosis, neurodegeneration, inflammation, free radicals
MeSH terms
Frataxin, Animals, Biological Transport, Humans, Iron, Transferrin, Oxidative Stress, Iron Overload, Iron-Binding Proteins, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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