Overview of iron metabolism in health and disease

Som Dev, Jodie L Babitt, Som Dev, Jodie L Babitt

Abstract

Iron is an essential element for numerous fundamental biologic processes, but excess iron is toxic. Abnormalities in systemic iron balance are common in patients with chronic kidney disease and iron administration is a mainstay of anemia management in many patients. This review provides an overview of the essential role of iron in biology, the regulation of systemic and cellular iron homeostasis, how imbalances in iron homeostasis contribute to disease, and the implications for chronic kidney disease patients.

Keywords: Iron metabolism; anemia; chronic kidney disease; iron deficiency; iron overload.

Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

JLB has ownership interest in Ferrumax Pharmaceuticals, Inc. SD has nothing to declare.

© 2017 International Society for Hemodialysis.

Figures

Figure 1. Systemic iron homeostasis
Figure 1. Systemic iron homeostasis
Iron (Fe) circulates in the bloodstream bound to transferrin (TF). The majority of iron is delivered to the bone marrow for red blood cell (RBC) production, with lesser amounts going to other tissues for fundamental cellular processes and the excess transported to the liver for storage. Systemic iron homeostasis is maintained predominantly by recycling iron from RBCs via reticuloendothelial macrophages. A smaller amount of iron is provided by dietary absorption via duodenal enterocytes, which is matched by an unregulated loss of iron through desquamation and blood loss.
Figure 2. Cellular iron homeostasis
Figure 2. Cellular iron homeostasis
Depicted cell is an amalgam of many cell types; not all proteins/pathways are present in all cells. Iron enters into cells primarily by transferrin receptor 1 (TFR1)-mediated endocytosis. In endosomes, iron is freed from TF and reduced by a ferriductase (STEAP3) before exiting into the cytosol via divalent metal transporter (DMT1). TF and TFR1 are recycled back to the cell membrane for further cycles. DMT1 and other transporters (ZIP8, ZIP14) function in non-TF bound iron (NTBI) uptake pathways in some cell types. Other iron acquisition pathways in some cell types include uptake of hemoglobin(Hb)-haptoglobin, heme-hemopexin, heme, lipocalin 2, and ferritin via CD163, CD91, FLVCR2, SLC22A17, SCARA5, and TIM2 receptors respectively. In the cytosol, iron enters the labile iron pool (LIP), and is then utilized, stored, or exported out of the cell. Cytoplasmic iron transport is assisted in some cases by the chaperone poly (rC) binding protein 1 (PCBP1). Iron is mainly utilized by mitochondria for heme synthesis and iron-sulfur clusters (ISCs) biogenesis, with mitoferrins (MFRN1/2) playing a role in mitochondrial iron import and FLVCR1B playing a role in mitochondrial heme export. Excess iron in the cytosol is stored safely in ferritin. A mitochondrial form of ferritin (MTFT) is also expressed in some cell types. When the demand arises, ferritin can be targeted for autophagic turnover by nuclear receptor coactivator 4 (NCOA4) to release iron into the cytosolic LIP. Iron is exported out of the cell by ferroportin (FPN), assisted by ferroxidases ceruloplasmin (CP)/hephaestin (HP), followed by iron loading onto TF. FLVCR1A may play a role in heme export in some cell types.
Figure 3. Regulation of cellular iron homeostasis.…
Figure 3. Regulation of cellular iron homeostasis. A
Under iron-deficient conditions, iron regulatory proteins (IRPs) bind to iron-responsive elements (IREs) in the 5′ untranslated regions (UTR) of iron homeostasis mRNAs such as ferritin (FTH1, FTL1) and ferroportin (FPN) to block their translation, while IRP binding in the 3′ UTR of TFR1 and DMT1 enhances mRNA stability. This leads to an increase in iron uptake and a decrease in iron storage and export. Under the iron-replete conditions, the IRP-IRE interaction is inhibited: IRP2 is targeted for proteasomal degradation by F-box/leucine-rich repeat protein 5 (FBXL5), and IRP1 gets converted into cytosolic aconitase. B. Under low iron and oxygen (O2) conditions, the regulatory hypoxia-inducible factor alpha subunit (HIFα) forms a complex with the ubiquitously expressed β subunit and translocates to the nucleus to regulate transcription of numerous iron homeostasis genes including TFR1, DMT1, FPN, CP, and erythropoietin (EPO). On the contrary, under iron-replete, normoxic conditions, HIFα subunits are targeted for proteasomal degradation by the oxygen- and iron-dependent prolyl hydroxylases (PHDs) and von Hippel-Lindau (VHL) protein. Abbreviations: ALAS, 5′-Aminolevulinate Synthase 2; Asc, ascorbate; UQ, ubiquitin; HRE, hypoxia response element; HO-1, heme oxygenase 1.
Figure 4. Regulation of systemic iron homeostasis
Figure 4. Regulation of systemic iron homeostasis
Secreted by the liver, hepcidin is a key iron hormone controls iron entry into circulation from absorptive enterocytes and iron-recycling macrophages by inducing FPN degradation. Iron loading and inflammation stimulate hepcidin transcription to prevent iron overload and sequester iron from pathogenic microorganisms (left panel). Iron deficiency and erythropoietic drive inhibit hepcidin transcription to provide adequate iron for erythropoiesis and other body requirements (right panel). Mediators of hepcidin regulation by iron, inflammation, and erythropoietic drive are indicated. Abbreviations: BMP, bone morphogenetic protein; HFE, hemochromatosis protein; TFR2, transferrin receptor 2; HJV, hemojuvelin; TMPRSS6 transmembrane protease serine 6; IL-6, interleukin 6; JAK, janus kinase; STAT3, signal transducer and activator of transcription 3; ERFE, erythroferrone.

References

    1. Martin W, Russell MJ. On the origins of cells: a hypothesis for the evolutionary transitions from abiotic geochemistry to chemoautotrophic prokaryotes, and from prokaryotes to nucleated cells. Philos Trans R Soc Lond B Biol Sci. 2003;358(1429):59–83.
    1. Evstatiev R, Gasche C. Iron sensing and signalling. Gut. 2012;61(6):933–952.
    1. Pietrangelo A. Pathogens, Metabolic Adaptation, and Human Diseases–An Iron-Thrifty Genetic Model. Gastroenterology. 2015;149(4):834–838.
    1. Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2011;283(2–3):65–87.
    1. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93(4):1721–1741.
    1. Pantopoulos K, Porwal SK, Tartakoff A, Devireddy L. Mechanisms of mammalian iron homeostasis. Biochemistry. 2012;51(29):5705–5724.
    1. Yang J, Mori K, Li JY, Barasch J. Iron, lipocalin, and kidney epithelia. Am J Physiol Renal Physiol. 2003;285(1):F9–18.
    1. McKie AT, Barrow D, Latunde-Dada GO, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science. 2001;291:1755–1759.
    1. Fleming MD, Trenor CC, III, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16:383–386.
    1. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-ion transporter. Nature. 1997;388:482–488.
    1. Gunshin H, Fujiwara Y, Custodio AO, et al. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest. 2005;115:1258–1266.
    1. Shawki A, Engevik MA, Kim RS, et al. Intestinal brush-border Na+/H+ exchanger-3 drives H+-coupled iron absorption in the mouse. Am J Physiol Gastrointest Liver Physiol. 2016;311(3):G423–430.
    1. Weintraub LR, Weinstein MB, Huser HJ, et al. Absorption of hemoglobin iron: the role of a heme-splitting substance in the intestinal mucosa. J Clin Invest. 1968;47:531–539.
    1. Theil EC, Chen H, Miranda C, et al. Absorption of iron from ferritin is independent of heme iron and ferrous salts in women and rat intestinal segments. J Nutr. 2012;142(3):478–483.
    1. Arosio P, Carmona F, Gozzelino R, Maccarinelli F, Poli M. The importance of eukaryotic ferritins in iron handling and cytoprotection. Biochem J. 2015;472(1):1–15.
    1. Vanoaica L, Darshan D, Richman L, Schümann K, Kühn LC. Intestinal ferritin H is required for an accurate control of iron absorption. Cell Metab. 2010;12(3):273–282.
    1. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403:776–781.
    1. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275:19906–19912.
    1. McKie AT, Marciani P, Rolfs A, et al. A novel duodenal ironregulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell. 2000;5:299–309.
    1. Drakesmith H, Nemeth E, Ganz T. Ironing out Ferroportin. Cell Metab. 2015;22(5):777–87.
    1. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet. 1999;21:195–199.
    1. 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(19):10812–10817.
    1. Cherukuri S, Potla R, Sarkar J, Nurko S, Harris ZL, Fox PL. Unexpected role of ceruloplasmin in intestinal iron absorption. Cell Metab. 2005;2(5):309–319.
    1. Nai A, Lidonnici MR, Rausa M, et al. The second transferrin receptor regulates red blood cell production in mice. Blood. 2015;125(7):1170–1179.
    1. Wood JC. Guidelines for quantifying iron overload. Hematology Am Soc Hematol Educ Program. 2014;2014(1):210–215.
    1. Jenkitkasemwong S, Wang CY, Coffey R, et al. SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis. Cell Metab. 2015;22(1):138–150.
    1. Cohen LA, Gutierrez L, Weiss A, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010;116(9):1574–1584.
    1. Meyron-Holtz EG, Moshe-Belizowski S, Cohen LA. A possible role for secreted ferritin in tissue iron distribution. J Neural Transm (Vienna) 2011;118(3):337–347.
    1. Bao G, Clifton M, Hoette TM, et al. Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat Chem Biol. 2010;6(8):602–609.
    1. Shi H, Bencze KZ, Stemmler TL, Philpott CC. A cytosolic iron chaperone that delivers iron to ferritin. Science. 2008;320(5880):1207–1210.
    1. Babcock M, de Silva D, Oaks R, et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science. 1997;276(5319):1709–1712.
    1. Shaw GC, Cope JJ, Li L, et al. Mitoferrin is essential for erythroid iron assimilation. Nature. 2006;440(7080):96–100.
    1. Chiabrando D, Marro S, Mercurio S, et al. The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation. J Clin Invest. 2012;122(12):4569–4579.
    1. Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 2014;509(7498):105–109.
    1. Mancias JD, Pontano Vaites L, Nissim S, et al. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. Elife. 2015;4
    1. Keel SB, Doty RT, Yang Z, et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science. 2008;319(5864):825–828.
    1. Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron-responsive element/ironregulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr. 2008;28:197–213.
    1. Vashisht AA, Zumbrennen KB, Huang X, et al. Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science. 2009;326(5953):718–721.
    1. Salahudeen AA, Thompson JW, Ruiz JC, et al. An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science. 2009;326(5953):722–726.
    1. Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle. 2008;7(1):28–32.
    1. Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC. Acute postnatal ablation of Hif-2α results in anemia. Proc Natl Acad Sci U S A. 2007;104(7):2301–2306.
    1. Shah YM, Matsubara T, Ito S, Yim SH, Gonzalez FJ. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 2009;9(2):152–164.
    1. Taylor M, Qu A, Anderson ER, et al. Hypoxia-inducible factor-2α mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology. 2011;140(7):2044–2055.
    1. Anderson SA, Nizzi CP, Chang YI, et al. The IRP1-HIF-2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab. 2013;17(2):282–290.
    1. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–2093.
    1. Zumerle S, Mathieu JR, Delga S, et al. Targeted disruption of hepcidin in the liver recapitulates the hemochromatotic phenotype. Blood. 2014;123(23):3646–3650.
    1. Wang CY, Babitt JL. Hepcidin regulation in the anemia of inflammation. Curr Opin Hematol. 2016;23(3):189–197.
    1. WHO Global Database on Anaemia. de Benoist Bruno, McLean Erin, Egli Ines, Cogswell Mary., editors. World prevalence of anaemia 1993–2005. Geneva: World Health Organization; 2008.
    1. Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. Iron deficiency anaemia. Lancet. 2016;387(10021):907–916.
    1. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47(5 suppl 3):S1–145.
    1. Zumbrennen-Bullough K, Babitt JL. The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients. Nephrol Dial Transplant. 2014;29(2):263–273.
    1. Mims MP, Guan Y, Pospisilova D, et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005;105(3):1337–1342.
    1. Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of atransferrinemia. Blood. 2000;96(13):4071–4074.
    1. Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RT, Gitlin JD. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci U S A. 1995;92(7):2539–2543.
    1. Finberg KE, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA) Nat Genet. 2008;40(5):569–571.
    1. Du X, She E, Gelbart T, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320(5879):1088–1092.
    1. Pietrangelo A. Iron and the liver. Liver Int. 2016;36(Suppl 1):116–123.
    1. Camaschella C, Nai A. Ineffective erythropoiesis and regulation of iron status in iron loading anaemias. Br J Haematol. 2016;172(4):512–523.
    1. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33(1):21–22.
    1. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399–408.
    1. Camaschella C, Roetto A, Calì A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25(1):14–15.
    1. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36(1):77–82.
    1. Drakesmith H, Schimanski LM, Ormerod E, et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood. 2005;106(3):1092–1097.
    1. 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(4):619–23.
    1. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46(7):678–684.
    1. Karaboyas A, Zee J, Morgenstern H, et al. Understanding the Recent Increase in Ferritin Levels in United States Dialysis Patients: Potential Impact of Changes in Intravenous Iron and Erythropoiesis-Stimulating Agent Dosing. Clin J Am Soc Nephrol. 2015;10:1814–1821.
    1. McClain DA, Abraham D, Rogers J, et al. High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis. Diabetologia. 2006;49(7):1661–1669.
    1. Vogiatzi MG, Macklin EA, Trachtenberg FL, et al. Thalassemia Clinical Research Network. Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America. Br J Haematol. 2009;146(5):546–556.
    1. Ford ES, Cogswell ME. Diabetes and serum ferritin concentration among U.S. adults. Diabetes Care. 1999;22(12):1978–1983.
    1. Jiang R, Ma J, Ascherio A, Stampfer MJ, Willett WC, Hu FB. Dietary iron intake and blood donations in relation to risk of type 2 diabetes in men: a prospective cohort study. Am J Clin Nutr. 2004;79(1):70–75.
    1. Song Y, Manson JE, Buring JE, Liu S. A prospective study of red meat consumption and type 2 diabetes in middle-aged and elderly women: the women’s health study. Diabetes Care. 2004;27(9):2108–2115.
    1. Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA. 2004;291(6):711–717.
    1. Dymock IW, Cassar J, Pyke DA, Oakley WG, Williams R. Observations on the pathogenesis, complications and treatment of diabetes in 115 cases of haemochromatosis. Am J Med. 1972;52(2):203–210.
    1. Platis O1, Anagnostopoulos G, Farmaki K, Posantzis M, Gotsis E, Tolis G. Glucose metabolism disorders improvement in patients with thalassaemia major after 24–36 months of intensive chelation therapy. Pediatr Endocrinol Rev. 2004;2(Suppl 2):279–281.
    1. Fernández-Real JM, Peñarroja G, Castro A, García-Bragado F, Hernández-Aguado I, Ricart W. Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes. 2002;51(4):1000–1004.
    1. Simcox JA, McClain DA. Iron and diabetes risk. Cell Metab. 2013;17(3):329–341.
    1. Cooksey RC, Jouihan HA, Ajioka RS, et al. Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. Endocrinology. 2004;145(11):5305–5312.
    1. Gabrielsen JS, Gao Y, Simcox JA, et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest. 2012;122(10):3529–3540.
    1. Pennell DJ, Udelson JE, Arai AE, et al. American Heart Association Committee on Heart Failure and Transplantation of the Council on Clinical Cardiology and Council on Cardiovascular Radiology and Imaging. Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013;128(3):281–308.
    1. Murphy CJ, Oudit GY. Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment. J Card Fail. 2010;16(11):888–900.
    1. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165:575–582 e573.
    1. Comin-Colet J, Enjuanes C, Gonzalez G, et al. Iron deficiency is a key determinant of health-related quality of life in patients with chronic heart failure regardless of anaemia status. Eur J Heart Fail. 2013;15:1164–1172.
    1. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–2448.
    1. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36(11):657–668.
    1. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet. 1981;1(8233):1293–1294.
    1. Ascherio A, Willett WC, Rimm EB, Giovannucci EL, Stampfer MJ. Dietary iron intake and risk of coronary disease among men. Circulation. 1994;89(3):969–974.
    1. van der ADL, Peeters PH, Grobbee DE, Marx JJ, van der Schouw YT. Dietary haem iron and coronary heart disease in women. Eur Heart J. 2005;26(3):257–262.
    1. Kiechl S, Willeit J, Egger G, Poewe W, Oberhollenzer F. Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study. Circulation. 1997;96(10):3300–3307.
    1. Danesh J, Appleby P. Coronary heart disease and iron status: meta-analyses of prospective studies. Circulation. 1999;99(7):852–854.
    1. Kuo KL, Hung SC, Lee TS, Tarng DC. Iron sucrose accelerates early atherogenesis by increasing superoxide production and upregulating adhesion molecules in CKD. J Am Soc Nephrol. 2014;25(11):2596–2606.
    1. Sullivan JL. Iron in arterial plaque: modifiable risk factor for atherosclerosis. Biochim Biophys Acta. 2009;1790(7):718–723.
    1. Kautz L, Gabayan V, Wang X, et al. Testing the iron hypothesis in a mouse model of atherosclerosis. Cell Rep. 2013;5(5):1436–1442.
    1. Bailie GR, Larkina M, Goodkin DA, et al. Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality. Kidney Int. 2015;87(1):162–168.
    1. Kshirsagar AV, Freburger JK, Ellis AR, Wang L, Winkelmayer WC, Brookhart MA. Intravenous iron supplementation practices and short-term risk of cardiovascular events in hemodialysis patients. PLoS One. 2013;8(11):e78930.
    1. Miskulin DC, Tangri N, Bandeen-Roche K, et al. Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network Patient Outcomes in End Stage Renal Disease Study Investigators. Intravenous iron exposure and mortality in patients on hemodialysis. Clin J Am Soc Nephrol. 2014;9(11):1930–1939.
    1. Moos T, Rosengren Nielsen T, Skjørringe T, Morgan EH. Iron trafficking inside the brain. J Neurochem. 2007;103(5):1730–1740.
    1. Beard J. Iron deficiency alters brain development and functioning. J Nutr. 2003;133(5 Suppl 1):1468S–1472S.
    1. Youdim MB. Brain iron deficiency and excess; cognitive impairment and neurodegeneration with involvement of striatum and hippocampus. Neurotox Res. 2008;14(1):45–56.
    1. Singh N, Haldar S, Tripathi AK, et al. Brain iron homeostasis: from molecular mechanisms to clinical significance and therapeutic opportunities. Antioxid Redox Signal. 2014;20(8):1324–1363.
    1. Poujois A, Devedjian JC, Moreau C, et al. Bioavailable Trace Metals in Neurological Diseases. Curr Treat Options Neurol. 2016;18(10):46.
    1. Rouault TA. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci. 2013;14(8):551–564.
    1. Chen K, Lin G, Haelterman NA, et al. Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration. Elife. 2016;5
    1. Rogers JT, Randall JD, Cahill CM, et al. An iron-responsive element type II in the 5′-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem. 2002;277(47):45518–45528.
    1. Friedlich AL, Tanzi RE, Rogers JT. The 5′-untranslated region of Parkinson’s disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry. 2007;12(3):222–223.
    1. Duce JA, Tsatsanis A, Cater MA, et al. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell. 2010;142(6):857–867.
    1. Wong BX, Tsatsanis A, Lim LQ, Adlard PA, Bush AI, Duce JA. β-Amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin. PLoS One. 2014;9(12):e114174.
    1. Salazar J, Mena N, Hunot S, et al. Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci U S A. 2008;105(47):18578–18583.
    1. Jin L, Wang J, Zhao L, et al. Decreased serum ceruloplasmin levels characteristically aggravate nigral iron deposition in Parkinson’s disease. Brain. 2011;134(Pt 1):50–8.
    1. Fracanzani AL, Conte D, Fraquelli M, et al. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology. 2001;33(3):647–651.
    1. Osborne NJ, Gurrin LC, Allen KJ, et al. HFE C282Y homozygotes are at increased risk of breast and colorectal cancer. Hepatology. 2010;51(4):1311–1318.
    1. Borgna-Pignatti C, Vergine G, Lombardo T, et al. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol. 2004;124(1):114–117.
    1. Manz DH, Blanchette NL, Paul BT, Torti FM, Torti SV. Iron and cancer: recent insights. Ann N Y Acad Sci. 2016;1368(1):149–161.
    1. Bystrom LM, Rivella S. Cancer cells with irons in the fire. Free Radic Biol Med. 2015;79:337–342.
    1. Pinnix ZK, Miller LD, Wang W, et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med. 2010;2(43):43ra56.
    1. Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373(9674):1532–1542.
    1. Pfeffer MA, Burdmann EA, Chen CY, et al. TREAT Investigators A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019–2032.
    1. Baliga R, Ueda N, Shah SV. Increase in bleomycin-detectable iron in ischaemia/reperfusion injury to rat kidneys. Biochem J. 1993;291(Pt 3):901–905.
    1. Baliga R, Zhang Z, Baliga M, Ueda N, Shah SV. In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Kidney Int. 1998;53(2):394–401.
    1. Nankivell BJ, Boadle RA, Harris DC. Iron accumulation in human chronic renal disease. Am J Kidney Dis. 1992;20:580–584.
    1. Wang H, Nishiya K, Ito H, Hosokawa T, Hashimoto K, Moriki T. Iron deposition in renal biopsy specimens from patients with kidney diseases. Am J Kidney Dis. 2001;38:1038–1044.
    1. Naito Y, Sawada H, Oboshi M, et al. Increased renal iron accumulation in hypertensive nephropathy of salt-loaded hypertensive rats. PLoS One. 2013;8:e75906.
    1. Linkermann A, Skouta R, Himmerkus N, et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A. 2014;111(47):16836–16841.
    1. Scindia Y, Dey P, Thirunagari A, et al. Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis. J Am Soc Nephrol. 2015;26(11):2800–2814.
    1. Paller MS, Hedlund BE. Role of iron in postischemic renal injury in the rat. Kidney Int. 1988;34(4):474–480.
    1. Zarjou A, Bolisetty S, Joseph R, et al. Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury. J Clin Invest. 2013;123(10):4423–4434.
    1. Nath KA. Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues. Kidney Int. 2006;70(3):432–443.
    1. Zager RA, Johnson AC, Frostad KB. Combined iron sucrose and protoporphyrin treatment protects against ischemic and toxin-mediated acute renal failure. Kidney Int. 2016;90(1):67–76.
    1. Guggenbuhl P, Deugnier Y, Boisdet JF, et al. Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Osteoporos Int. 2005;16(12):1809–1814.
    1. Vogiatzi MA, Macklin EA, Fung EB, et al. Bone disease in thalassemia: a frequent and still unresolved problem. J Bone Miner Res. 2009;24(3):543–557.
    1. Mahachoklertwattana P, Sirikulchayanonta V, Chuansumrit A, et al. Bone histomorphometry in children and adolescents with beta-thalassemia disease: iron-associated focal osteomalacia. J Clin Endocrinol Metab. 2003;88(8):3966–3972.
    1. David V, Francis C, Babitt JL. Ironing out the cross talk between FGF23 and inflammation. Am J Physiol Renal Physiol. 2017;312(1):F1–F8.
    1. David V, Martin A, Isakova T, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2016;89(1):135–146.
    1. Farrow EG, Yu X, Summers LJ, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci USA. 2011;108:E1146–E1155.
    1. Imel EA, Peacock M, Gray AK, et al. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011;96:3541–3549.
    1. Ganz T, Nemeth E. Iron homeostasis in host defence and inflammation. Nat Rev Immunol. 2015;15:500–510.
    1. Arezes J, Jung G, Gabayan V, et al. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe. 2015;17:47–57.
    1. Sazawal S, Black RE, Ramsan M, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006;367(9505):133–143.
    1. Soofi S, Cousens S, Iqbal SP, et al. Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial. Lancet. 2013;382(9886):29–40.
    1. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. Br Med J. 1978;2(6145):1113–1135.
    1. Darton TC, Blohmke CJ, Giannoulatou E, et al. Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans. PLoS Negl Trop Dis. 2015;9:e0004029.
    1. Kim DK, Jeong JH, Lee JM, et al. Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat Med. 2014;20:419–424.
    1. Wang L, Harrington L, Trebicka E, et al. Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice. J Clin Invest. 2009;119(11):3322–3328.
    1. Pagani A, Nai A, Corna G, et al. Low hepcidin accounts for the proinflammatory status associated with iron deficiency. Blood. 2011;118(3):736–746.
    1. Nairz M, Haschka D, Demetz E, Weiss G. Iron at the interface of immunity and infection. Front Pharmacol. 2014;5:152.
    1. Macdougall IC, Bircher AJ, Eckardt KU, et al. Conference Participants. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2016;89(1):28–39.

Source: PubMed

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