OUTLINE OF IRON METABOLISM, WITH EMPHASIS TO ERYTHROID CELLS iron Metabolism
Main Article Content
Keywords
Iron; Ferritin; Ferroportin; DMT1; Hepcidin
Abstract
Iron is required for several vital biological processes in all human cells. In mammals, a considerable number of proteins are involved in iron metabolism and utilize iron in many essential cellular processes, such as oxygen transport, mitochondrial respiration, gene regulation and DNA synthesis or repair. Iron metabolism is a complex system finely regulated at both systemic and cellular levels. It involves the development of specialized mechanisms for iron absorption, transport, recycling, storage and export, and protection against toxic compounds that can be generated during iron redox cycling in the presence of oxygen.
The erythropoietic compartment consumes the majority of iron to support the high demand for hemoglobin synthesis. A tightly regulated system enables efficient iron uptake by erythroid cells and its subsequent processing for the synthesis of large amounts of heme, which is then incorporated into hemoglobin. A bidirectional regulatory system between erythropoiesis and iron metabolism ensures precise coordination between the two processes. This regulation is often disrupted in various anemic conditions.
Keywords : Iron; Ferritin; Ferroportin; DMT1; Hepcidin
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References
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1. Comprubi E, Jordan SF, Vasiliadou R, Lane N. Iron catalysis at the origin of life. IUBMB Life 2017; 69: 373-381.
2. Ganz T. Systemic iron homeostasis. Physiol Rev 2013; 93: 1721-1741.
3. Correnti, M.; Gammella, E.; Cairo, G.; Recalcati, S. Iron absorption: molecular and pathophysiological aspects. Metabolites 2024; 14, 228.
4. Gunshin, H.; Fujiwara, Y.; Custodio, A.O.; Direnzo, C.; Robine, S.; Andrews, N.C. Slc11a2 is required form intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 2005; 115, 1258-1266.
5. Heoda J, Shah A, Zhang L. Heme, an essential nutrient from dietary proteins, critically impacts diverse physiological and pathological processes. Nutrients 2014; 6: 1080-1102.
6. Kenny TC, Khan A, Son Y, Yue L, Heissel S, Sharma A, Pasolli HA, Liu Y, Gamazon ER, Alwaseem H, et al. Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals. Cell Metab 2023; 35, 1057-1071.
7. Pan, Y.; Ron, Z.; Gao, S.; Shen, J.; Wang, L.; Xu, Z.; Yu, Y.; Bachina, P.; Zhang, H.; Pan, X.; et al. Structural basis of iron transport and inhibition in ferroportin. Nat Commun 2020, 11, 5686.
8. Donovan AS.; Lima, C.A.; Pinkus, J.L.; Pinkus, G.S.; Zon, L.I.; Robine, S.; Andrews, N.C. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005, 1, 191-200.
9. Balusikova, K.; Dustalikova-Cimburova, M.; Tachechi, I.; Kovar, J. Expression profiles of iron transport molecules along the duodenum. J Cell Mol Med 2022, 26, 2995-3004.
10. Nemeth, E.; Ganz, T. Hepcidin and iron in health and disease. Ann Rev Med 2023, 74, 261-277.
11. Drakesmith, H.; Nemeth, E.; Ganz, T. Ironing out ferroportin. Cell Metab 2015, 22, 777-787.
12. Mastrogiannaki M, Matak P, Keith B, Simon C, Vauloint S, Peyssonnaux C. HIF-2, promotes iron absorption in mice. J Clin Invest 2019, 119, 1159-1166.
13. Schwartz A, Das NK, Ramakrishnan S, Jain C, Jurkovitch MT, Mu J, Nemeth E, Lakhal-Littleton S, Colacino JA, Shah YM. Hepatic hepcidin/intestinal HIF-2 axis maintains iron absorption during iron deficiency and overload. J Clin Invest 2019,; 129, 336-348.
14. Zhang, D.L.; Hughes, R.M.; Ollivierre-Wilson, H.; Ghosh, M.C.; Rouault, T.A. A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab 20’09, 9, 461-473.
15. Recalcati, S.; Cairo, G. Macrophages and iron: a special relationship. Biomedicines 2024, 9, 1585.
16. Korolnek, T.; Hamza, I. Macrophages and iron trafficking at the birth and death of red cells. Blood 2015, 125, 2893-2897.
17. Zhang Z, Zhang F, An P, Guo X, Shen Y, Tao Y, Wu Q, Zhang Y, Yu Y, Ning B, et al. Ferroportin 1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 2011; 118: 1912-1922.
18. Knutson MD, Oukka M, Koss LM, Aydemir F, Wessling-Resnick M. Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci USA 2005; 102: 1324-1328.
19. DSi Rumo SC, Check IJ, Hunter RL. Quantitation of apo-, mono-, and differric transferrin by polyacrylamide gradient electrophoresis in patients with disorders of iron metabolism. Blood 1985; 66: 1445-1451.
20. Sposi NM, Cianetti L, Tritarelli E, Pelosi E, Militi S, Barberi T, Gabbianelli M, Saulle E, Kuhn L, Peschle C, Testa U. Mechanisms of differential transferrin receptor expression in normal hematopoiesis. Eur J Biochem 2000; 267: 6762-6774.
21. Nai A, Lindonnici MR, Rausa M. The second transferrin receptor regulates red blood cell production in mice. Blood 2015; 125: 1170-1179.
22. West AP, Bennett MJ, Sellers VM, Andrews NC, Enns CA, Bjorkman PJ. Comparison of the interactions of transferrin receptor 1 and transferrin receptor 2 with transferrin and the hereditary hemochromatosis HFE. J Biol Chem 2000; 275: 38135-38138.
23. Riedel HD, Muckenthaler MU, Gehrke SG, Mohr I, Brennan K, Herrmann T, Fitscher BA, Hentze MW, Stremmel W. HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. Blood 1999; 94: 3915-3921.
24. Fillebeen C, Charlebois E, Wagner J, Katsarou A, Mui J, Vali H, Garcia-Santos D, Ponka P, Presle J, Pantopoulos K. Transferrin receptor 1 controls systemic iron homeostasis by fine-tuning hepcidin expression to hepatocellular iron load. Blood 2019; 133: 344-355.
25. Wallace DF, Summerville L, Subramaniam VN, Targeted disruption of the hepatic transferrin receptor 2 gene in mice leads to iron overload. Gastroenterology 2007; 132: 301-310.
26. Xiao X, Moschetta GA, Xu Y, Fisher AL, Alfaro-Magallanes VM, Dev S, Wang CY, Babitt JL. Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in -thalassemia. Blood 2023; 141: 422-431.
27. Levy JE, Jin D, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and nervous system. Nat Genet 1999; 21: 396-399.
28. Wang S, He X, Wu Q, Jiang L, Chen L, Yu Y, Zhang P, Huang X, Wang J, et al. Transferrin receptor 1-mediated iron uptake plays an essential role in hematopoiesis. Haematologica 2020; 105: 2071-2082.
29. Das A, Nag S, Mason AB, Barroso MM. Endosome-mitochondria interactions are modulated by iron release from transferrin. J Cell Biol 2016; 214: 831-845.
30. Hamdi A, Roshan TM, Kahawita TM, Mason AB, Sheftel AD, Ponka P. Erythroid cell mitochondria receive endosomal iron by a “kiss-and-run” mechanism. Biochim Biophys Acta 2016; 1863: 2859-2867.
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Aug 31, 2025
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Testa, U., Pelosi, E. and Castelli, G. (2025) “OUTLINE OF IRON METABOLISM, WITH EMPHASIS TO ERYTHROID CELLS: iron Metabolism”, Mediterranean Journal of Hematology and Infectious Diseases, 17(1), p. e2025067. doi: 10.4084/MJHID.2025.067.
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