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Cited by 1,001Iron Metabolism and DisordersNeurological diseases and metabolismTrace Elements in Health

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Regulation of cellular iron metabolism

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Wang, Jian, Pantopoulos, Kostas·2011·Biochemical Journal
DOI 10.1042/bj20101825PMC PMC3048577
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Abstract

Iron is an essential but potentially hazardous biometal. Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of haem or iron-sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Iron metabolism is controlled at different levels and by diverse mechanisms. The present review summarizes basic concepts of iron transport, use and storage and focuses on the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, a well known post-transcriptional regulatory circuit that not only maintains iron homoeostasis in various cell types, but also contributes to systemic iron balance.

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Figure 1 Hormonal regulation of iron efflux from duodenal enterocytes and reticuloendothelial macrophages by hepcidin Enterocytes absorb inorganic or haem iron from the diet and macrophages phagocytose iron-loaded senescent red blood cells, or acquire iron by other mechanisms (see the main text). Both cell types release Fe2+ into the plasma via ferroportin (Fpn), which is incorporated into apo-Tf following oxidation to Fe3+ via hephaestin (Heph) or ceruloplasmin (Cp). Hepatocytes generate the iron-regulatory hormone hepcidin in response to high iron or inflammatory signals, which inhibits the efflux of iron via ferroportin and promotes its retention within enterocytes and macrophages.
Figure 1 Hormonal regulation of iron efflux from duodenal enterocytes and reticuloendothelial macrophages by hepcidin Enterocytes absorb inorganic or haem iron from the diet and macrophages phagocytose iron-loaded senescent red blood cells, or acquire iron by other mechanisms (see the main text). Both cell types release Fe2+ into the plasma via ferroportin (Fpn), which is incorporated into apo-Tf following oxidation to Fe3+ via hephaestin (Heph) or ceruloplasmin (Cp). Hepatocytes generate the iron-regulatory hormone hepcidin in response to high iron or inflammatory signals, which inhibits the efflux of iron via ferroportin and promotes its retention within enterocytes and macrophages.CC BY-NC · PubMed Central
Figure 2 Cellular iron uptake via the Tf cycle Iron-loaded holo-Tf binds to TfR1 on the cell surface and the complex undergoes endocytosis via clathrin-coated pits. A proton pump acidifies the endosome, resulting in the release of Fe3+, which is subsequently reduced to Fe2+ by Steap3 and transported across the endosomal membrane to the cytosol by DMT1. Internalized iron is directed to mitochondria via mitoferrin for metabolic utilization (such as synthesis of haem and ISCs), and excess iron is stored in ferritin. A cytosolic fraction of redox-active intracellular iron constitutes the LIP. The apo-Tf–TfR1 complex is recycled to the cell surface, where apo-Tf is released to capture plasma Fe3+.
Figure 2 Cellular iron uptake via the Tf cycle Iron-loaded holo-Tf binds to TfR1 on the cell surface and the complex undergoes endocytosis via clathrin-coated pits. A proton pump acidifies the endosome, resulting in the release of Fe3+, which is subsequently reduced to Fe2+ by Steap3 and transported across the endosomal membrane to the cytosol by DMT1. Internalized iron is directed to mitochondria via mitoferrin for metabolic utilization (such as synthesis of haem and ISCs), and excess iron is stored in ferritin. A cytosolic fraction of redox-active intracellular iron constitutes the LIP. The apo-Tf–TfR1 complex is recycled to the cell surface, where apo-Tf is released to capture plasma Fe3+.CC BY-NC · PubMed Central
Figure 3 Typical IRE motif A typical IRE motif consists of a hexanucleotide loop with the sequence 5′-CAGUGH-3′ (H could be A, C, or U) and a stem, interrupted by a bulge with an unpaired C residue (left) or an asymmetric tetranucleotide bulge (right); the latter is characteristic of ferritin IRE. Base-pairing between C1 and G5 of the loop is functionally important.
Figure 3 Typical IRE motif A typical IRE motif consists of a hexanucleotide loop with the sequence 5′-CAGUGH-3′ (H could be A, C, or U) and a stem, interrupted by a bulge with an unpaired C residue (left) or an asymmetric tetranucleotide bulge (right); the latter is characteristic of ferritin IRE. Base-pairing between C1 and G5 of the loop is functionally important.CC BY-NC · PubMed Central
Figure 4 Post-transcriptional control of cellular pathways by the IRE–IRP regulatory system Translational-type IRE–IRP interactions in the 5′UTR modulate the expression of the mRNAs encoding H- and L-ferritin, ALAS2, m-aconitase, ferroportin, HIF-2α, β-APP and α-synuclein, which in turn control iron storage, erythroid iron utilization, energy homoeostasis, iron efflux, hypoxic responses and neurological pathways respectively. Conversely, IRE–IRP interactions in the 3′UTR stabilize the mRNAs encoding TfR1, DMT1, Cdc14A and MRCKα, which are involved in iron uptake, iron transport, the cell cycle and cytoskeletal remodelling respectively. Note that the regulation of DMT1, Cdc14A and MRCKα may require additional factors, and that the IREs in Cdc14A and MRCKα mRNAs are not phylogenetically conserved.
Figure 4 Post-transcriptional control of cellular pathways by the IRE–IRP regulatory system Translational-type IRE–IRP interactions in the 5′UTR modulate the expression of the mRNAs encoding H- and L-ferritin, ALAS2, m-aconitase, ferroportin, HIF-2α, β-APP and α-synuclein, which in turn control iron storage, erythroid iron utilization, energy homoeostasis, iron efflux, hypoxic responses and neurological pathways respectively. Conversely, IRE–IRP interactions in the 3′UTR stabilize the mRNAs encoding TfR1, DMT1, Cdc14A and MRCKα, which are involved in iron uptake, iron transport, the cell cycle and cytoskeletal remodelling respectively. Note that the regulation of DMT1, Cdc14A and MRCKα may require additional factors, and that the IREs in Cdc14A and MRCKα mRNAs are not phylogenetically conserved.CC BY-NC · PubMed Central
Figure 5 Crystal structure of IRP1 (A) c-Aconitase form (PDB code 2B3X); (B) IRE-binding form (PDB code 2IPY). A three-dimensional structure of this Figure is available at http://www.BiochemJ.org/bj/434/0365/bj4340365add.htm.
Figure 5 Crystal structure of IRP1 (A) c-Aconitase form (PDB code 2B3X); (B) IRE-binding form (PDB code 2IPY). A three-dimensional structure of this Figure is available at http://www.BiochemJ.org/bj/434/0365/bj4340365add.htm.CC BY-NC · PubMed Central
Figure 6 Under physiological conditions, IRP1 is regulated by a reversible ISC switch Iron deficiency promotes ISC disassembly and a conformational rearrangement, resulting in the conversion of IRP1 from c-aconitase to an IRE-binding protein. The ISC is regenerated in iron-replete cells. Hypoxia favours maintenance of the ISC, whereas H2O2 or NO promote its disassembly. When the ISC-biogenesis pathway is not operational, iron leads to ubiquitination of apo-IRP1 by the FBXL5 E3 ligase complex (including Skp1, Cul1 and Rbx1), resulting in proteasomal degradation.
Figure 6 Under physiological conditions, IRP1 is regulated by a reversible ISC switch Iron deficiency promotes ISC disassembly and a conformational rearrangement, resulting in the conversion of IRP1 from c-aconitase to an IRE-binding protein. The ISC is regenerated in iron-replete cells. Hypoxia favours maintenance of the ISC, whereas H2O2 or NO promote its disassembly. When the ISC-biogenesis pathway is not operational, iron leads to ubiquitination of apo-IRP1 by the FBXL5 E3 ligase complex (including Skp1, Cul1 and Rbx1), resulting in proteasomal degradation.CC BY-NC · PubMed Central
Figure 7 Iron and oxygen-dependent regulation of IRP2 stability by FBXL5 IRP2 is stable in iron deficient and/or hypoxic cells; under these conditions, FBXL5 undergoes ubiquitination and proteasomal degradation. An increase in iron and oxygen levels stabilizes FBXL5 by formation of an Fe–O–Fe centre in its haemerythrin domain, triggering the assembly of an E3 ubiquitin ligase complex together with Skp1, Cul1 and Rbx1. This complex ubiquitinates (Ub) IRP2, leading to its recognition by the proteasome and its degradation.
Figure 7 Iron and oxygen-dependent regulation of IRP2 stability by FBXL5 IRP2 is stable in iron deficient and/or hypoxic cells; under these conditions, FBXL5 undergoes ubiquitination and proteasomal degradation. An increase in iron and oxygen levels stabilizes FBXL5 by formation of an Fe–O–Fe centre in its haemerythrin domain, triggering the assembly of an E3 ubiquitin ligase complex together with Skp1, Cul1 and Rbx1. This complex ubiquitinates (Ub) IRP2, leading to its recognition by the proteasome and its degradation.CC BY-NC · PubMed Central

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Metadata

Authors
Wang, J., & Pantopoulos, K.
Affiliations
Jewish General Hospital (CA)
Corresponding author
Pantopoulos, Kostas
ORCID
Pantopoulos, Kostas
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2011-02-24
Volume
434
Issue
3
Pages
365-381
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
DOI
10.1042/bj20101825
PMC
PMC3048577
OpenAlex
W2158115535
Cited by
986
References
208
Citations by year
2026: 38 · 2025: 41 · 2024: 54 · 2023: 72 · 2022: 69 · 2021: 70 · 2020: 71 · 2019: 72 · 2018: 67 · 2017: 64 · 2016: 56 · 2015: 67 · 2014: 77 · 2013: 76 · 2012: 60
FWCI
10.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochemical Journal (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research (MOP-86514)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords
iron homeostasis, transferrin, transferrin receptor 1, iron absorption, endocytosis, mitochondrial iron transport, haem synthesis, iron-sulfur clusters, ferritin, iron storage, post-transcriptional regulation
MeSH terms
Animals, Biological Transport, Ferritins, Humans, Iron, Mitochondria, Neoplasms, Oxidation-Reduction, RNA, Messenger, Transferrin, Response Elements, Iron-Regulatory Proteins

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