Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“In conjunction with this dichromatic nature, both severe iron overload and iron deficiency may be deleterious.”

In the paper

“iron deficiency is a serious problem that causes cell damage, reduction of cell growth and proliferation, hypoxia, and death.”

In the paper

“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.”

In the paper

“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”

In the paper

“Furthermore, TfR2 is not redundant for TfR1, for TfR1 knockout is embryonically lethal (184), despite the presence of TfR2.”

What the sources say

• Not checked yetcites [184] Levy JE. Jin O. Fujiwara Y. Kuo F. Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21:396–399. doi: 10.1038/7727. [DOI] [PubMed] [Google Scholar] source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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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In the paper

“Two different TfRs, TfR1 and TfR2, are expressed and serve as gatekeepers for iron-bound Tf (Fe-Tf) (Fig. 1).”

In the paper

“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).”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [140] Iwai K. Drake SK. Wehr NB. Weissman AM. LaVaute T. Minato N. Klausner RD. Levine RL. Rouault TA. Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins. Proc Natl Acad Sci U S A. 1998;95:4924–4928. doi: 10.1073/pnas.95.9.4924. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper

“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).”

What the sources say

• Not checked yetcites [314] Waheed A. Grubb JH. Zhou XY. Tomatsu S. Fleming RE. Costaldi ME. Britton RS. Bacon BR. Sly WS. Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci U S A. 2002;99:3117–3122. doi: 10.1073/pnas.042701499. [DOI] [PMC free article] [PubMed] [Google Scholar]

In the paper

“For example, during heme-mediated gene regulation, heme induces IRP2 oxidation on Cys201, which is followed by enhanced IRP2 degradation (328).”

What the sources say

• Not checked yetcites [328] Yamanaka K. Ishikawa H. Megumi Y. Tokunaga F. Kanie M. Rouault TA. Morishima I. Minato N. Ishimori K. Iwai K. Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2. Nat Cell Biol. 2003;5:336–340. doi: 10.1038/ncb952. [DOI] [PubMed] [Google Scholar]

In the paper

“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).”

What the sources say

• Not checked yetcites [41] Casey JL. Hentze MW. Koeller DM. Caughman SW. Rouault TA. Klausner RD. Harford JB. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science. 1988;240:924–928. doi: 10.1126/science.2452485. [DOI] [PubMed] [Google Scholar]
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In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

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

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [117] Gunshin H. Mackenzie B. Berger UV. Gunshin Y. Romero MF. Boron WF. Nussberger S. Gollan JL. Hediger MA. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482–488. doi: 10.1038/41343. [DOI] [PubMed] [Google Scholar] source

In the paper

“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).”

What the sources say

• Not checked yetcites [1] Abboud S. Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275:19906–19912. doi: 10.1074/jbc.M000713200. [DOI] [PubMed] [Google Scholar] source
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In the paper

“The DMT1B promoter contains a putative NF-κB element, and NF-κB bound to this response element during differentiation (231).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [106] Gitlin JD. Aceruloplasminemia. Pediatr Res. 1998;44:271–276. doi: 10.1203/00006450-199809000-00001. [DOI] [PubMed] [Google Scholar] source

In the paper

“DMT1A is expressed mainly in the duodenum and in epithelial cells, whereas DMT1B is expressed predominantly in erythroid cells (38, 39).”

What the sources say

• Not checked yetcites [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 yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“Years later, it was revealed that Cp has ferroxidase activity and catalyzes the oxidation of Fe2+ to Fe3+ (228) (see Fig. 4).”

What the sources say

• Not checked yetcites [228] Osaki S. Kinetic studies of ferrous ion oxidation with crystalline human ferroxidase (ceruloplasmin) J Biol Chem. 1966;241:5053–5059. [PubMed] [Google Scholar]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“Fpn (also termed Ireg1, MTP1) was originally identified by positional cloning to identify the causative gene for hypochromic anemia of “weissherbst” mutant zebrafish (72).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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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In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

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In the paper

“HFE2 is a BMP coreceptor, and its mutation suppresses BMP signaling (14).”

What the sources say

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In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“when Cp was absent, Fe2+ remained bound to Fpn, leading to ubiquitination on Fpn Lys253 (65).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“Fpn degradation is abrogated by oxidation, depletion of extracellular Fe2+, or mutation of Lys253 to Ala (65).”

What the sources say

• Not checked yetcites [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]

In the paper

“Once inside the cell, Fpn is ubiquitinated after dephosphorylation, and ultimately, Fpn undergoes degradation in the lysosome (Fig. 6) (66).”

What the sources say

• Not checked yetcites [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

In the paper

“H expression is abundant in the heart, whereas the L subunit is predominant in the liver and spleen (125).”

What the sources say

• Not checked yetcites [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

In the paper

“the synthesized ferritins consist of only L-subunit homopolymers (85), which lack ferroxidase activity and has lower iron-incorporation capability (183).”

What the sources say

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In the paper

“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).”

What the sources say

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In the paper

“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).”

What the sources say

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In the paper

“Ferritin H is induced by NF-κB in response to TNF-α treatment, resulting in suppression of ROS and inhibition of apoptosis (243).”

What the sources say

• Not checked yetcites [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

In the paper

“Ferritin H and L subunits are encoded by two different genes (322).”

What the sources say

• Not checked yetcites [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]

In the paper

“Smad4-knockout mice had lower levels of hepcidin and did not induce hepcidin in response to iron loading or IL-6 stimulation (14).”

What the sources say

• Not checked yetcites [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

In the paper

“the ferritin L subunit stabilizes ferritin structure and facilitates the uptake of iron into the shell (9).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“administration of soluble HJV inhibited BMP-mediated induction of hepcidin and resulted in increased levels of Fpn in vivo (15).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

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In the paper

“Several studies showed that ferritin also binds to erythroid precursors (100), brain tissue (138), and placental microvilli membranes (186).”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“Serum ferritin is identical to cytoplasmic ferritin, but the primary component of serum ferritin is the ferritin L subunit, which contains little iron (323).”

What the sources say

• Not checked yetcites [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

In the paper

“The highest expression level was observed in testis; other tissue has very little expression (74, 182).”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“Lysosome-mediated ferritin degradation uses the autophagy system under particular conditions (173, 226) and iron chelator treatment (165)”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“It appears that Fpn expression enhances ferritin degradation via a proteasomal degradation-dependent pathway, because proteasome inhibitors treatment prevented ferritin degradation (64).”

What the sources say

• Not checked yetcites [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]

In the paper

“Ferritoid is a 30-kDa protein consisting of 270 amino acids specifically expressed in corneal epithelial cells (201).”

What the sources say

• Not checked yetcites [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

In the paper

“IRP2-knockout mice showed abnormal induction of ferritin expression, resulting in iron misregulation in intestinal mucosa and the CNS (55, 200).”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“iron binding to IRP1 competes with IRP1–IRE interaction, so that increased iron levels in cells enhances translation of ferritin proteins (317).”

What the sources say

• Not checked yetcites [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]

In the paper

“the binding of this mutant ferritin H to DNA was lower and less effective for the protection of DNA from UV damage”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“H2O2-induced oxidative stress and phorbol 12-myristate 13-acetate (PMA) have been shown to modulate the activity of IRP1 and IRP2 (269).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“tBHQ, sulforaphane, hemin, and high levels of iron activated this element (133)”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“NF-κB is activated by TNF-α and has been shown to induce mouse and human ferritin H (171, 243).”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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]
• Not checked yetcites [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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In the paper

“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)”

What the sources say

• Not checked yetcites [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]

In the paper

“Nrf2 disruption in mice enhanced susceptibility to severe airway inflammation, asthma, and cigarette smoke–induced emphysema (253, 254)”

What the sources say

• Not checked yetcites [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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In the paper

“Nrf2-knockout mice developed normally and survived to adult stage”

What the sources say

• Not checked yetcites [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]

In the paper

“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.”

In the paper

“Frataxin is a nuclear-encoded mitochondrial protein conserved from yeast to human (166), but with no homology with proteins of known functional domains.”

What the sources say

• Not checked yetcites [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

In the paper

“It was demonstrated that yeast mature frataxin directly binds iron (2), in which iron triggers assembly of frataxin oligomerization.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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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In the paper

“The same research group generated frataxin-overexpressing mice, which also showed normal iron metabolism with no signs of abnormalities (203).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“It was demonstrated that the skeletal muscle of FRDA patients had impaired mitochondrial respiration and a profound deficit of ATP production (189)”

What the sources say

• Not checked yetcites [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]

In the paper

“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)”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“These mice exhibited a reduced life span and development of multiple hepatic tumor growths (289).”

What the sources say

• Not checked yetcites [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]

In the paper

“Homozygous deletions in the frataxin gene in mice caused embryonic lethality, indicating an important role of frataxin in mouse development (57).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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)”

What the sources say

• Not checked yetcites [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]

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“The GAA repeat in FRDA patients ranges from 100 to >1,000 repeats, whereas normal individuals have fewer than 35 repeats (37).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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.”

In the paper

“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)”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“In yeast, it was demonstrated that frataxin is involved in mitochondrial iron efflux (252) or iron storage (96, 234).”

What the sources say

• Not checked yetcites [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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In the paper

“The most abundant frataxin mRNA is a transcript from exon 1 to exon 5a, with a size of 1.3 kb (37).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites Table 2

In the paper

“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.”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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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In the paper

“The human frataxin gene is located on chromosome 9 (q13-q21.1) consisting of seven exons spanning >95 kb of the genomic DNA (37).”

What the sources say

• Not checked yetcites [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

In the paper

“which was rescued by treatment with the iron chelator deferoxamine (321) or by near-physiologic levels of frataxin expression (287).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“In human mature frataxin, the structure is compact, with no signature of iron binding or oligomerization in the presence of iron (212)”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“whereas the mature human frataxin was reported to assemble in >600-kDa homopolymers and bind ∼10 atoms of iron per frataxin oligomer (44).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“Hereditary hemochromatosis (HH) is the most common form of iron-overload disorder in individuals of northern European descent (299).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“HFE2 is a GPI-anchored protein that appears to be a sensor of dietary iron levels (230).”

What the sources say

• Not checked yetcites [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

In the paper

“In a mouse model for FRDA, the antioxidant Idebenone delayed the onset of cardiac dysfunction without improvement of deficiency in ISC proteins (274).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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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In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“Further studies demonstrated that the C282Y HFE mutant is retained in the ER and Golgi and is rapidly degraded (316).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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]
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In the paper

“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).”

What the sources say

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In the paper

“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).”

What the sources say

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In the paper

“Initially, the deleterious effects of iron loading are not clinically significant, and manifest as discomfort in hand joints, increased skin pigmentation, and fatigue (16).”

What the sources say

• Not checked yetcites [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]

In the paper

“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.”

In the paper

“Iron deficiency may have deleterious effects on neurotransmission, myelination, and dopamine receptor and transporter functions (18).”

What the sources say

• Not checked yetcites [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

In the paper

“Type 3 HH is pathophysiologically similar to type 1; however, it occurs as a result of a mutation in TfR2 (34).”

What the sources say

• Not checked yetcites [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]

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

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In the paper

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

In the paper

“Studies have shown that TfR2 does not associate with HFE, suggesting an alternative role for TfR2 mutation in HH (320).”

What the sources say

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In the paper

“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).”

What the sources say

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In the paper

“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).”

What the sources say

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In the paper

“This form of HH is autosomal dominant in nature, and various missense mutations lead to altered Fpn (92, 205, 218).”

What the sources say

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In the paper

“The D544E Cp was expressed at lower levels and exhibited decreased ferroxidase activity (135).”

What the sources say

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In the paper

“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).”

What the sources say

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In the paper

“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.”

What the sources say

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In the paper

“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.”

What the sources say

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In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

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In the paper

“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.”

What the sources say

• Not checked yetcites [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]

In the paper

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

What the sources say

• Not checked yetcites [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