The IRP1-HIF-2α Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption
Open accessAbstract
Red blood cell production is a finely tuned process that requires coordinated oxygen- and iron-dependent regulation of cell differentiation and iron metabolism. Here, we show that translational regulation of hypoxia-inducible factor 2α (HIF-2α) synthesis by iron regulatory protein 1 (IRP1) is critical for controlling erythrocyte number. IRP1-null (Irp1(-/-)) mice display a marked transient polycythemia. HIF-2α messenger RNA (mRNA) is derepressed in kidneys of Irp1(-/-) mice but not in kidneys of Irp2(-/-) mice, leading to increased renal erythropoietin (Epo) mRNA and inappropriately elevated serum Epo levels. Expression of the iron transport genes DCytb, Dmt1, and ferroportin, as well as other HIF-2α targets, is enhanced in Irp1(-/-) duodenum. Analysis of mRNA translation state in the liver revealed IRP1-dependent dysregulation of HIF-2α mRNA translation, whereas IRP2 deficiency derepressed translation of all other known 5' iron response element (IRE)-containing mRNAs expressed in the liver. These results uncover separable physiological roles of each IRP and identify IRP1 as a therapeutic target for manipulating HIF-2α action in hematologic, oncologic, and other disorders.
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When the mechanism fails, as in Irp1-knockout mice, a transient polycythemia occurs in the relatively iron-deficient young animals, which reverts in adult mice with iron sufficiency.
“When the mechanism fails, as in Irp1-knockout mice, a transient polycythemia occurs in the relatively iron-deficient young animals, which reverts in adult mice with iron sufficiency.64,65”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [65]
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Cites
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380 · see citing works
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693 · see citing works
Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641 · see citing works
Iron-dependent regulation of the divalent metal ion transporter
Gunshin, H., Allerson, C. R., Polycarpou-Schwarz, M., Rofts, A., Rogers, J. T., Kishi, F., Hentze, M. W., Rouault, T. A., Andrews, N. C., & Hediger, M. A. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03189-1 · Cited by 305 · see citing works
Self-citationIron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency
Sanchez, M., Galy, B., Muckenthaler, M. U., & Hentze, M. W. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1222 · Cited by 294 · see citing works
Self-citationTaylor, M., Qu, A., Anderson, E. R., Matsubara, T., Martin, A., Gonzalez, F. J., & Shah, Y. M. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.03.007 · Cited by 265 · see citing works
Tong, W.-H., Sourbier, C., Kovtunovych, G., Jeong, S. Y., Vira, M., Ghosh, M., Romero, V. V., Sougrat, R., Vaulont, S., Viollet, B., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.07.018 · Cited by 212 · see citing works
Zimmer, M., Ebert, B. L., Neil, C., Brenner, K., Papaioannou, I., Melas, A., Tolliday, N., Lamb, J., Pantopoulos, K., Golub, T., et al. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.12.004 · Cited by 191 · see citing works
A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo
Minamishima, Y. A., Moslehi, J., Padera, R. F., Bronson, R. T., Liao, R., & Kaelin, W. G. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00331-09 · Cited by 161 · see citing works
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A Red carpet for iron metabolism
Muckenthaler, M. U., Rivella, S., Hentze, M. W., & Galy, B. (2017) · Cell · doi:10.1016/j.cell.2016.12.034 · Cited by 1,319 · see citing works
Self-citationIron metabolism and iron disorders revisited in the hepcidin era
Camaschella, C., Nai, A., & Silvestri, L. (2020) · Haematologica · doi:10.3324/haematol.2019.232124 · Cited by 734 · see citing works
“When the mechanism fails, as in Irp1-knockout mice, a transient polycythemia occurs in the relatively iron-deficient young animals, which reverts in adult mice with iron sufficiency.(64,65) In this context prolyl hydroxylase, the enzyme that induces degradation of HIF-2α, is irondependent and is thus inactive in iron…”
Camaschella, C. (2019) · Blood · doi:10.1182/blood-2018-05-815944 · Cited by 702 · see citing works
Mechanistic and regulatory aspects of intestinal iron absorption
Gulec, S., Anderson, G. J., & Collins, J. F. (2014) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00348.2013 · Cited by 406 · see citing works
The IRP/IRE system in vivo: insights from mouse models
Wilkinson, N., & Pantopoulos, K. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00176 · Cited by 366 · see citing works
Liver iron sensing and body iron homeostasis
Wang, C.-Y., & Babitt, J. L. (2019) · Blood · doi:10.1182/blood-2018-06-815894 · Cited by 360 · see citing works
Anaemia in kidney disease: harnessing hypoxia responses for therapy
Koury, M. J., & Haase, V. H. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.82 · Cited by 313 · see citing works
Iron deficiency: new insights into diagnosis and treatment
Camaschella, C. (2015) · Hematology · doi:10.1182/asheducation-2015.1.8 · Cited by 201 · see citing works
Hypoxia-inducible factors link iron homeostasis and erythropoiesis
Shah, Y. M., & Xie, L. (2014) · Gastroenterology · doi:10.1053/j.gastro.2013.12.031 · Cited by 187 · see citing works
Minihepcidin peptides as disease modifiers in mice affected by β-thalassemia and polycythemia vera
Casu, C., Oikonomidou, P. R., Chen, H., Nandi, V., Ginzburg, Y., Prasad, P., Fleming, R. E., Shah, Y. M., Valore, E. V., Nemeth, E., et al. (2016) · Blood · doi:10.1182/blood-2015-10-676742 · Cited by 148 · see citing works
The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions
Mastrogiannaki, M., Matak, P., & Peyssonnaux, C. (2013) · Blood · doi:10.1182/blood-2012-11-427765 · Cited by 116 · see citing works
Zhang, D.-L., Ghosh, M. C., Ollivierre, H., Li, Y., & Rouault, T. A. (2018) · Blood · doi:10.1182/blood-2018-04-842997 · Cited by 107 · see citing works
Iron regulatory proteins control a mucosal block to intestinal iron absorption
Galy, B., Ferring-Appel, D., Becker, C., Gretz, N., Gröne, H.-J., Schümann, K., & Hentze, M. W. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.02.026 · Cited by 98 · see citing works
Self-citationOral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia
Manolova, V., Nyffenegger, N., Flace, A., Altermatt, P., Varol, A., Doucerain, C., Sundstrom, H., & Dürrenberger, F. (2019) · Journal of Clinical Investigation · doi:10.1172/jci129382 · Cited by 98 · see citing works
Compartmentalization of iron between mitochondria and the cytosol and its regulation
Mühlenhoff, U., Hoffmann, B., Richter, N., Rietzschel, N., Spantgar, F., Stehling, O., Uzarska, M. A., & Lill, R. (2015) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2015.05.003 · Cited by 95 · see citing works
Diagnosis of iron-deficient states
Archer, N. M., & Brugnara, C. (2015) · Critical Reviews in Clinical Laboratory Sciences · doi:10.3109/10408363.2015.1038744 · Cited by 82 · see citing works
Shanmugam, N. K. N., Trebicka, E., Fu, L.-L., Shi, H. N., & Cherayil, B. J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400278 · Cited by 49 · see citing works
Iron regulatory protein-1 protects against mitoferrin-1-deficient porphyria
Chung, J., Anderson, S. A., Gwynn, B., Deck, K. M., Chen, M. J., Langer, N. B., Shaw, G. C., Huston, N. C., Boyer, L. F., Datta, S., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.547778 · Cited by 39 · see citing works
Self-citation
- Authors
- Anderson, S. A., Nizzi, C. P., Chang, Y.-I., Deck, K. M., Schmidt, P. J., Galy, B., Damnernsawad, A., Broman, A. T., Kendziorski, C., Hentze, M. W., Fleming, M. D., Zhang, J., & Eisenstein, R. S.
- Affiliations
- University of Wisconsin–Madison (US)
- Boston Children's Hospital (US)
- European Molecular Biology Laboratory (DE)
- Corresponding author
- Zhang, Jing
- Eisenstein, Richard S.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 17
- Issue
- 2
- Pages
- 282-290
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3612289
- OpenAlex
- W2042212143
- Cited by
- 211
- References
- 9
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 13 · 2023: 14 · 2022: 11 · 2021: 17 · 2020: 19 · 2019: 19 · 2018: 18 · 2017: 14 · 2016: 10 · 2015: 23 · 2014: 23 · 2013: 9
- FWCI
- 14.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- V Foundation for Cancer Research
- University of Wisconsin-Madison (R01CA152108, WIS01324)
- Greater Milwaukee Foundation
- National Institutes of Health (R01 DK66600)
- National Center for Research Resources (1UL1RR025011)
- National Cancer Institute (P30 CA014520)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- iron regulatory protein 1, HIF-2α, IRP2, erythropoiesis, iron absorption, iron metabolism, oxygen sensing, erythropoietin, polycythemia, iron-responsive element, translational regulation, ferroportin, DMT1, Dcytb, kidney, duodenum, liver
- MeSH terms
- Absorption, Endothelial PAS Domain-Containing Protein 1, Animals, Duodenum, Erythropoiesis, Erythropoietin, Gene Expression Regulation, Hematopoiesis, Extramedullary, Iron, Oxygen, Polycythemia, RNA, Messenger, Spleen, Protein Biosynthesis, Signal Transduction, Erythroid Precursor Cells, Iron Regulatory Protein 1, Erythroid Cells, Mice, Basic Helix-Loop-Helix Proteins
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