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Two to Tango: Regulation of Mammalian Iron Metabolism
Open accessAbstract
Disruptions in iron homeostasis from both iron deficiency and overload account for some of the most common human diseases. Iron metabolism is balanced by two regulatory systems, one that functions systemically and relies on the hormone hepcidin and the iron exporter ferroportin, and another that predominantly controls cellular iron metabolism through iron-regulatory proteins that bind iron-responsive elements in regulated messenger RNAs. We describe how the two distinct systems function and how they "tango" together in a coordinated manner. We also highlight some of the current questions in mammalian iron metabolism and discuss therapeutic opportunities arising from a better understanding of the underlying biological principles.
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“It is worth noting that SF is a marker of acute and chronic inflammatory conditions that can be markedly elevated in persons with average iron storage in many different medical conditions, such as rheumatoid arthritis, systemic lupus erythematosus, chronic kidney disease, hepatitis, excessive alcohol consumption, heart failure, acute infection, intestinal disorders such as coeliac disease, obesity”
From Defining Global Thresholds for Serum Ferritin: A Challenging Mission in Establishing the Iron Deficiency Diagnosis in This Era of Striving for Health Equity (2025) · cites this paper as [11]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Under physiological conditions iron recycling by macrophages accounts for approximately 95% of the daily needs of the metal for erythropoiesis and other physiological processes (Hentze et al., 2010; Pantopoulos et al., 2012).”
From Iron at the interface of immunity and infection (2014) · cites this paper as Hentze et al., 2010
In the citing paper
“Hepcidin expression is inhibited by iron deficiency, expansion of erythropoiesis, anemia/hypoxia, testosterone and possibly other factors.1,47”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [1]
In the citing paper
“When intracellular iron is low, IRPs interact with conserved iron-responsive elements (IREs) in the untranslated regions (UTRs) of central genes accounting for iron homeostasis [32,33].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [32]
In the citing paper
“The amount of the LIP is sensed by post-transcriptional mechanisms of cytosolic iron-regulated RNA binding proteins 1 and 2 (IRP-1 and IRP-2) to fine-tune uptake, storage, and release of iron.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [32]
In the citing paper
“Binding of IRPs to IREs in the 5’-UTR attenuates translation, whereas binding to IREs in the 3’-UTR stabilizes respective mRNAs and fosters translation.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [32]
In the citing paper
“However, gel retardation assays demonstrated that LPS stimulation increased binding of iron-regulatory proteins (IRPs) to a radiolabeled iron responsive element (IRE) RNA probe (Figure 3B), indicative of reduced cytosolic Fe availability (Hentze et al., 2010).”
From Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen (2015) · cites this paper as Hentze et al., 2010
In the citing paper
“This appears to be the result of increased expression of the master iron regulator hepcidin, which promotes Fpn1 internalization and degradation (1, 36).”
From Dopamine Is a Siderophore-Like Iron Chelator That Promotes Salmonella enterica Serovar Typhimurium Virulence in Mice (2019) · cites this paper as [1]
In the citing paper
“Due to this relatively inefficient process, iron stores, particularly ferritin-associated iron in liver and spleen, can become depleted during chronic bleeding episodes, repetitive blood donations, helminth infestations, through materno-fetal transfer, or during growth [5].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [5]
In the citing paper
“Peripheral cellular iron uptake mainly involves endocytosis of the diferric transferrin–transferrin receptor 1 (TFR1; panel) complex; iron is then transported from the endosomes into the cell cytoplasm via the divalent metal ion transporter 1 (DMT1; panel).”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [2]
In the citing paper
“Iron homoeostasis is needed to maintain normal physiological brain function, whereas misregulation of iron homoeostasis can cause neurotoxicity through different mechanisms.”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [2]
In the citing paper
“Iron homoeostasis is needed to maintain normal physiological brain function, whereas misregulation of iron homoeostasis can cause neurotoxicity through different mechanisms.”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [2]
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Metadata
- Authors
- Hentze, M. W., Muckenthaler, M. U., Galy, B., & Camaschella, C.
- Affiliations
- Heidelberg University (DE)
- European Molecular Biology Laboratory (DE)
- Vita-Salute San Raffaele University (IT)
- Corresponding author
- Hentze, Matthias W.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 142
- Issue
- 1
- Pages
- 24-38
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2107704801
- Cited by
- 2,120
- References
- 111
- Citations by year
- 2026: 98 · 2025: 117 · 2024: 161 · 2023: 169 · 2022: 156 · 2021: 162 · 2020: 159 · 2019: 159 · 2018: 129 · 2017: 125 · 2016: 106 · 2015: 118 · 2014: 133 · 2013: 113 · 2012: 113
- FWCI
- 16.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, cc-by)
- Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- iron metabolism, iron homeostasis, hepcidin, ferroportin, iron regulatory proteins, iron-responsive element, iron deficiency, iron overload, therapeutic target
- MeSH terms
- Animals, Cell Physiological Phenomena, Humans, Iron, Anemia, Iron-Deficiency, Iron Overload, Antimicrobial Cationic Peptides, Hepcidins
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