Transfusion Medicine Reviews
Volume 23, Issue 2 , Pages 103-123 , April 2009

Blood Iron Homeostasis: Newly Discovered Proteins and Iron Imbalance

References 

  1. Crichton RR, Pierre JL. Old iron, young copper: From Mars to Venus. Biometals. 2001;14:99–112
  2. Harris WR. In:  Templeton D editors. Molecular and cellular iron transport. New York: Marcel Dekker Inc.; 2002;p. 1–40
  3. Pierre JL, Fontecave M. Iron and activated oxygen species in biology: The basic chemistry. Biometals. 1999;12:195–199
  4. Lippard SJ, Beng JM. Principles of Bioinorganic Chemistry. Mill Valley (Calif): University Science Books; 1994;
  5. Radisky D, Kaplan J. Regulation of transition metal transport across the yeast plasma membrane. J Biol Chem. 1999;274:4481–4484
  6. Aisen P, Enns C, Wessling-Resnick M. Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol. 2001;33:940–959
  7. Mason SF. Origin of the Elements, Molecules and Living Systems. Oxford, UK: Clarendon Press; 1991;
  8. Burbridge E, Burbridge G, Fowler W, et al. Synthesis of the elements in stars. Rev Mod Phys. 1957;29:547–650
  9. Askwith C, Kaplan J. Iron and copper transport in yeast and its relevance to human disease. Trends Biochem Sci. 1998;23:135–138
  10. Anderson GJ, Frazer DM, McKie AT, et al. Mechanisms of haem and non-haem iron absorption: Lessons from inherited disorders of iron metabolism. Biometals. 2005;18:339–348
  11. Sharp P, Srai SK. Molecular mechanisms involved in intestinal iron absorption. World J Gastroenterol. 2007;13:4716–4724
  12. Umbreit J. Iron deficiency: A concise review. Am J Hematol. 2005;78:225–231
  13. Conrad ME, Umbreit JN. Pathways of iron absorption. Blood Cells Mol Dis. 2002;29:336–355
  14. Fleming RE. Advances in understanding the molecular basis for the regulation of dietary iron absorption. Curr Opin Gastroenterol. 2005;21:201–206
  15. Bothwell TH, Baynes RD, MacFarlane BJ, et al. Nutritional iron requirements and food iron absorption. J Intern Med. 1989;226:357–365
  16. Skikne BS, Lynch SR, Cook JD. Role of gastric acid in food iron absorption. Gastroenterology. 1981;81:1068–1071
  17. Conrad ME, Umbreit JN. Iron absorption and transport—An update. Am J Hematol. 2000;64:287–298
  18. Umbreit JN, Conrad ME, Hainsworth LN, et al. The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin. Am J Physiol Gastrointest Liver Physiol. 2002;282:G534–G539
  19. Fleming MD, Trenor CC, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16:383–386
  20. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482–488
  21. 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
  22. Lam-Yuk-Tseung S, Govoni G, Forbes J, et al. Iron transport by Nramp2/DMT1: pH regulation of transport by 2 histidines in transmembrane domain 6. Blood. 2003;101:3699–3707
  23. Courville P, Chaloupka R, Cellier MF. Recent progress in structure-function analyses of Nramp proton-dependent metal-ion transporters. Biochem Cell Biol. 2006;84:960–978
  24. Cohen A, Nevo Y, Nelson N. The first external loop of the metal ion transporter DCT1 is involved in metal ion binding and specificity. Proc Natl Acad Sci U S A. 2003;100:10694–10699
  25. Li H, Li F, Kwan M, et al. NMR Structures and orientation of the fourth transmembrane domain of the rat divalent metal transporter (DMT1) with G185D mutation in SDS micelles. Biopolymers. 2005;77:173–183
  26. Nevo Y, Nelson N. The mutation F227I increases the coupling of metal ion transport in DCT1. J Biol Chem. 2004;279:53056–53061
  27. Mackenzie B, Ujwal ML, Chang MH, et al. Divalent metal-ion transporter DMT1 mediates both H+-coupled Fe2+ transport and uncoupled fluxes. Pflugers Arch. 2006;451:544–558
  28. Lee PL, Gelbart T, West C, et al. The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis. 1998;24:199–215
  29. Hubert N, Hentze MW. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function. Proc Natl Acad Sci U S A. 2002;99:12345–12350
  30. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: Molecular control of mammalian iron metabolism. Cell. 2004;117:285–297
  31. Tandy S, Williams M, Leggett A, et al. Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells. J Biol Chem. 2000;275:1023–1029
  32. Gunshin H, Allerson CR, Polycarpou-Schwarz M, et al. Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett. 2001;509:309–316
  33. Lam-Yuk-Tseung S, Gros P. Distinct targeting and recycling properties of two isoforms of the iron transporter DMT1 (NRAMP2, Slc11A2). Biochemistry. 2006;45:2294–2301
  34. 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
  35. Frazer DM, Wilkins SJ, Becker EM, et al. A rapid decrease in the expression of DMT1 and Dcytb but not Ireg1 or hephaestin explains the mucosal block phenomenon of iron absorption. Gut. 2003;52:340–346
  36. Latunde-Dada GO, Van der Westhuizen J, Vulpe CD, et al. Molecular and functional roles of duodenal cytochrome b (Dcytb) in iron metabolism. Blood Cells Mol Dis. 2002;29:356–360
  37. Gunshin H, Starr CN, Direnzo C, et al. Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood. 2005;106:2879–2883
  38. McKie AT, Latunde-Dada GO, Miret S, et al. Molecular evidence for the role of a ferric reductase in iron transport. Biochem Soc Trans. 2002;30:722–724
  39. Andrews NC, Schmidt PJ. Iron homeostasis. Annu Rev Physiol. 2007;69:69–85
  40. Hallberg L. Bioavailability of dietary iron in man. Annu Rev Nutr. 1981;1:123–147
  41. Wheby MS, Suttle GE, Ford KT. Intestinal absorption of hemoglobin iron. Gastroenterology. 1970;58:647–654
  42. Grasbeck R, Kouvonen I, Lundberg M, et al. An intestinal receptor for heme. Scand J Haematol. 1979;23:5–9
  43. Worthington MT, Cohn SM, Miller SK, et al. Characterization of a human plasma membrane heme transporter in intestinal and hepatocyte cell lines. Am J Physiol Gastrointest Liver Physiol. 2001;280:G1172–G1177
  44. Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell. 2005;122:789–801
  45. Rouault TA. The intestinal heme transporter revealed. Cell. 2005;122:649–651
  46. Latunde-Dada GO, Simpson RJ, McKie AT. Recent advances in mammalian haem transport. Trends Biochem Sci. 2006;31:182–188
  47. Krishnamurthy P, Xie T, Schuetz JD. The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther. 2007;114:345–358
  48. Latunde-Dada GO, Takeuchi K, Simpson RJ, et al. Haem carrier protein 1 (HCP1): Expression and functional studies in cultured cells. FEBS Lett. 2006;580:6865–6870
  49. Qiu A, Jansen M, Sakaris A, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006;127:917–928
  50. Conrad ME, Umbreit JN, Moore EG, et al. Alternate iron transport pathway. Mobilferrin and integrin in K562 cells. J Biol Chem. 1994;269:7169–7173
  51. Simovich M, Hainsworth LN, Fields PA, et al. Localization of the iron transport proteins mobilferrin and DMT-1 in the duodenum: The surprising role of mucin. Am J Hematol. 2003;74:32–45
  52. Umbreit JN, Conrad ME, Moore EG, et al. Paraferritin: A protein complex with ferrireductase activity is associated with iron absorption in rats. Biochemistry. 1996;35:6460–6469
  53. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403:776–781
  54. McKie AT, Marciani P, Rolfs A, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell. 2000;5:299–309
  55. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275:19906–19912
  56. Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis. 2004;32:131–138
  57. McKie AT, Barlow DJ. The SLC40 basolateral iron transporter family (IREG1/ferroportin/MTP1). Pflugers Arch. 2004;447:801–806
  58. Schimanski LM, Drakesmith H, Merryweather-Clarke AT, et al. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood. 2005;105:4096–4102
  59. Jeong SY, David S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem. 2003;278:27144–27148
  60. Han O, Kim EY. Colocalization of ferroportin-1 with hephaestin on the basolateral membrane of human intestinal absorptive cells. J Cell Biochem. 2007;101:1000–1010
  61. Mok H, Jelinek J, Pai S, et al. Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice. Development. 2004;131:1859–1868
  62. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–2093
  63. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1:191–200
  64. 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
  65. Chen H, Su T, Attieh ZK, et al. Systemic regulation of hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency. Blood. 2003;102:1893–1899
  66. Bannerman RM, Cooper RG. Sex-linked anemia: A hypochromic anemia of mice. Science. 1966;151:581–582
  67. Kuo YM, Su T, Chen H, et al. Mislocalisation of hephaestin, a multicopper ferroxidase involved in basolateral intestinal iron transport, in the sex linked anaemia mouse. Gut. 2004;53:201–206
  68. Li L, Vulpe CD, Kaplan J. Functional studies of hephaestin in yeast: evidence for multicopper oxidase activity in the endocytic pathway. Biochem J. 2003;375:793–798
  69. Bonaccorsi di Patti MC, Miele R, Eugenia Schinina M, et al. The yeast multicopper oxidase Fet3p and the iron permease Ftr1p physically interact. Biochem Biophys Res Commun. 2005;333:432–437
  70. De Domenico I, Ward DM, di Patti MC, et al. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. Embo J. 2007;26:2823–2831
  71. McGregor JA, Shayeghi M, Vulpe CD, et al. Impaired iron transport activity of ferroportin 1 in hereditary iron overload. J Membr Biol. 2005;206:3–7
  72. Hart EB, Steenbock H, Waddell J, et al. Iron in nutrition: VII. Copper as a supplement to iron for hemoglobin building in the rat. 1928. J Biol Chem. 2002;277:e22
  73. Roy CN, Enns CA. Iron homeostasis: New tales from the crypt. Blood. 2000;96:4020–4027
  74. Koury MJ, Ponka P. New insights into erythropoiesis: The roles of folate, vitamin B12, and iron. Annu Rev Nutr. 2004;24:105–131
  75. Jelkmann W. Erythropoietin after a century of research: Younger than ever. Eur J Haematol. 2007;78:183–205
  76. Goodnough LT. Erythropoietin and iron-restricted erythropoiesis. Exp Hematol. 2007;35:167–172
  77. Richardson DR, Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim Biophys Acta. 1997;1331:1–40
  78. Bullen J, Griffiths E, Rogers H, et al. Sepsis: The critical role of iron. Microbes Infect. 2000;2:409–415
  79. Johnson MB, Enns CA. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood. 2004;104:4287–4293
  80. Rothenberg BE, Voland JR. Beta2 knockout mice develop parenchymal iron overload: A putative role for class I genes of the major histocompatibility complex in iron metabolism. Proc Natl Acad Sci U S A. 1996;93:1529–1534
  81. Levy JE, Jin O, Fujiwara Y, et al. Transferrin receptor is necessary for development of RBCs and the nervous system. Nat Genet. 1999;21:396–399
  82. Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annu Rev Nutr. 2002;22:439–458
  83. Healy J, Tipton K. Ceruloplasmin and what it might do. J Neural Transm. 2007;114:777–781
  84. Harris ZL, Klomp LW, Gitlin JD. Aceruloplasminemia: An inherited neurodegenerative disease with impairment of iron homeostasis. Am J Clin Nutr. 1998;67:972S–977S
  85. Harris ZL, Takahashi Y, Miyajima H, et al. Aceruloplasminemia: Molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci U S A. 1995;92:2539–2543
  86. Gitlin JD. Aceruloplasminemia. Pediatr Res. 1998;44:271–276
  87. Madsen E, Gitlin JD. Copper and iron disorders of the brain. Annu Rev Neurosci. 2007;30:317–337
  88. Jabado N, Canonne-Hergaux F, Gruenheid S, et al. Iron transporter Nramp2/DMT-1 is associated with the membrane of phagosomes in macrophages and Sertoli cells. Blood. 2002;100:2617–2622
  89. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–1276
  90. Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu Rev Nutr. 2006;26:323–342
  91. Knutson MD, Oukka M, Koss LM, et al. Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci U S A. 2005;102:1324–1328
  92. Nairz M, Theurl I, Ludwiczek S, et al. The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell Microbiol. 2007;9:2126–2140
  93. Enns C. In:  Templeton D editors. Molecular and Cellular Iron Transport. New York: Marcel Decker Inc.; 2002;p. 71–94
  94. Dautry-Varsat A, Ciechanover A, Lodish HF. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc Natl Acad Sci U S A. 1983;80:2258–2262
  95. Bennett MJ, Lebron JA, Bjorkman PJ. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature. 2000;403:46–53
  96. Giannetti AM, Halbrooks PJ, Mason AB, et al. The molecular mechanism for receptor-stimulated iron release from the plasma iron transport protein transferrin. Structure. 2005;13:1613–1623
  97. McKie AT. A ferrireductase fills the gap in the transferrin cycle. Nat Genet. 2005;37:1159–1160
  98. Ohgami RS, Campagna DR, Greer EL, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37:1264–1269
  99. Fleming RE, Migas MC, Zhou X, et al. Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1. Proc Natl Acad Sci U S A. 1999;96:3143–3148
  100. Food MR, Rothenberger S, Gabathuler R, et al. Transport and expression in human melanomas of a transferrin-like glycosylphosphatidylinositol-anchored protein. J Biol Chem. 1994;269:3034–3040
  101. Richardson DR. The role of the membrane-bound tumour antigen, melanotransferrin (p97), in iron uptake by the human malignant melanoma cell. Eur J Biochem. 2000;267:1290–1298
  102. Dunn LL, Rahmanto YS, Richardson DR. Iron uptake and metabolism in the new millennium. Trends Cell Biol. 2007;17:93–100
  103. Woodbury RG, Brown JP, Yeh MY, et al. Identification of a cell surface protein, p97, in human melanomas and certain other neoplasms. Proc Natl Acad Sci U S A. 1980;77:2183–2187
  104. Brown JP, Woodbury RG, Hart CE, et al. Quantitative analysis of melanoma-associated antigen p97 in normal and neoplastic tissues. Proc Natl Acad Sci U S A. 1981;78:539–543
  105. Sekyere EO, Dunn LL, Richardson DR. Examination of the distribution of the transferrin homologue, melanotransferrin (tumour antigen p97), in mouse and human. Biochim Biophys Acta. 2005;1722:131–142
  106. Food MR, Sekyere EO, Richardson DR. The soluble form of the membrane-bound transferrin homologue, melanotransferrin, inefficiently donates iron to cells via nonspecific internalization and degradation of the protein. Eur J Biochem. 2002;269:4435–4445
  107. Dunn LL, Sekyere EO, Rahmanto YS, et al. The function of melanotransferrin: a role in melanoma cell proliferation and tumorigenesis. Carcinogenesis. 2006;27:2157–2169
  108. Sekyere E, Richardson DR. The membrane-bound transferrin homologue melanotransferrin: Roles other than iron transport?. FEBS Lett. 2000;483:11–16
  109. MacGillivray RT, Mason AB. In:  Templeton D editors. Molecular and Cellular Iron Transport. New York: Marcel Dekker Inc.; 2002;p. 95–123
  110. Ward PP, Paz E, Conneely OM. Multifunctional roles of lactoferrin: A critical overview. Cell Mol Life Sci. 2005;62:2540–2548
  111. Ward PP, Mendoza-Meneses M, Cunningham GA, et al. Iron status in mice carrying a targeted disruption of lactoferrin. Mol Cell Biol. 2003;23:178–185
  112. Coon MJ, Ding XX, Pernecky SJ, et al. Cytochrome P450: Progress and predictions. Faseb J. 1992;6:669–673
  113. Eklund H, Uhlin U, Farnegardh M, et al. Structure and function of the radical enzyme ribonucleotide reductase. Prog Biophys Mol Biol. 2001;77:177–268
  114. Shaw GC, Cope JJ, Li L, et al. Mitoferrin is essential for erythroid iron assimilation. Nature. 2006;440:96–100
  115. Li FY, Nikali K, Gregan J, et al. Characterization of a novel human putative mitochondrial transporter homologous to the yeast mitochondrial RNA splicing proteins 3 and 4. FEBS Lett. 2001;494:79–84
  116. Muhlenhoff U, Stadler JA, Richhardt N, et al. A specific role of the yeast mitochondrial carriers MRS3/4p in mitochondrial iron acquisition under iron-limiting conditions. J Biol Chem. 2003;278:40612–40620
  117. Zhang Y, Lyver ER, Knight SA, et al. Mrs3p, Mrs4p, and frataxin provide iron for Fe-S cluster synthesis in mitochondria. J Biol Chem. 2006;281:22493–22502
  118. Zhang Y, Lyver ER, Knight SA, et al. Frataxin and mitochondrial carrier proteins, Mrs3p and Mrs4p, cooperate in providing iron for heme synthesis. J Biol Chem. 2005;280:19794–19807
  119. Li L, Kaplan J. A mitochondrial-vacuolar signaling pathway in yeast that affects iron and copper metabolism. J Biol Chem. 2004;279:33653–33661
  120. Bulteau AL, O'Neill HA, Kennedy MC, et al. Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science. 2004;305:242–245
  121. Nichol H, Gakh O, O'Neill HA, et al. Structure of frataxin iron cores: An X-ray absorption spectroscopic study. Biochemistry. 2003;42:5971–5976
  122. Adamec J, Rusnak F, Owen WG, et al. Iron-dependent self-assembly of recombinant yeast frataxin: Implications for Friedreich ataxia. Am J Hum Genet. 2000;67:549–562
  123. Cavadini P, O'Neill HA, Benada O, et al. Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Hum Mol Genet. 2002;11:217–227
  124. Gakh O, Adamec J, Gacy AM, et al. Physical evidence that yeast frataxin is an iron storage protein. Biochemistry. 2002;41:6798–6804
  125. Park S, Gakh O, O'Neill HA, et al. Yeast frataxin sequentially chaperones and stores iron by coupling protein assembly with iron oxidation. J Biol Chem. 2003;278:31340–31351
  126. Yoon T, Cowan JA. Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins. J Am Chem Soc. 2003;125:6078–6084
  127. Lesuisse E, Santos R, Matzanke BF, et al. Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1). Hum Mol Genet. 2003;12:879–889
  128. Cook JD, Bencze KZ, Jankovic AD, et al. Monomeric yeast frataxin is an iron-binding protein. Biochemistry. 2006;45:7767–7777
  129. Gibson TJ, Koonin EV, Musco G, et al. Friedreich's ataxia protein: Phylogenetic evidence for mitochondrial dysfunction. Trends Neurosci. 1996;19:465–468
  130. Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: Distinct control mechanisms in erythroid cells. Blood. 1997;89:1–25
  131. Ponka P. Cell biology of heme. Am J Med Sci. 1999;318:241–256
  132. Lill R, Dutkiewicz R, Elsasser HP, et al. Mechanisms of iron-sulfur protein maturation in mitochondria, cytosol and nucleus of eukaryotes. Biochim Biophys Acta. 2006;1763:652–667
  133. Lill R, Muhlenhoff U. Iron-sulfur protein biogenesis in eukaryotes: components and mechanisms. Annu Rev Cell Dev Biol. 2006;22:457–486
  134. Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood. 2002;99:3505–3516
  135. Carrondo MA. Ferritins, iron uptake and storage from the bacterioferritin viewpoint. EMBO J. 2003;22:1959–1968
  136. Harrison PM. Ferritin: An iron-storage molecule. Semin Hematol. 1977;14:55–70
  137. Surguladze N, Patton S, Cozzi A, et al. Characterization of nuclear ferritin and mechanism of translocation. Biochem J. 2005;388:731–740
  138. Levi S, Arosio P. Mitochondrial ferritin. Int J Biochem Cell Biol. 2004;36:1887–1889
  139. Ghosh S, Hevi S, Chuck SL. Regulated secretion of glycosylated human ferritin from hepatocytes. Blood. 2004;103:2369–2376
  140. Hasan MR, Morishima D, Tomita K, et al. Identification of a 250 kDa putative microtubule-associated protein as bovine ferritin. Evidence for a ferritin-microtubule interaction. FEBS J. 2005;272:822–831
  141. Hasan MR, Koikawa S, Kotani S, et al. Ferritin forms dynamic oligomers to associate with microtubules in vivo: Implication for the role of microtubules in iron metabolism. Exp Cell Res. 2006;312:1950–1960
  142. Hentze MW, Kuhn LC. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci U S A. 1996;93:8175–8182
  143. Haile DJ, Rouault TA, Harford JB, et al. Cellular regulation of the iron-responsive element binding protein: Disassembly of the cubane iron-sulfur cluster results in high-affinity RNA binding. Proc Natl Acad Sci U S A. 1992;89:11735–11739
  144. Pantopoulos K. Iron metabolism and the IRE/IRP regulatory system: An update. Ann N Y Acad Sci. 2004;1012:1–13
  145. Rouault TA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol. 2006;2:406–414
  146. Vyoral D, Petrak J. Iron transport in K562 cells: A kinetic study using native gel electrophoresis and 59Fe autoradiography. Biochim Biophys Acta. 1998;1403:179–188
  147. Petrak JV, Vyoral D. Detection of iron-containing proteins contributing to the cellular labile iron pool by a native electrophoresis metal blotting technique. J Inorg Biochem. 2001;86:669–675
  148. Pufahl RA, Singer CP, Peariso KL, et al. Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science. 1997;278:853–856
  149. Culotta VC, Klomp LW, Strain J, et al. The copper chaperone for superoxide dismutase. J Biol Chem. 1997;272:23469–23472
  150. Beers J, Glerum DM, Tzagoloff A. Purification, characterization, and localization of yeast Cox17p, a mitochondrial copper shuttle. J Biol Chem. 1997;272:33191–33196
  151. Ponka P, Sheftel AD, Zhang AS. Iron targeting to mitochondria in erythroid cells. Biochem Soc Trans. 2002;30:735–738
  152. Li L, Chen OS, McVey Ward D, et al. CCC1 is a transporter that mediates vacuolar iron storage in yeast. J Biol Chem. 2001;276:29515–29519
  153. Valore EV, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis. 2007;
  154. Hunter HN, Fulton DB, Ganz T, et al. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002;277:37597–37603
  155. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A. 2001;98:8780–8785
  156. Nicolas G, Bennoun M, Porteu A, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A. 2002;99:4596–4601
  157. De Domenico I, Ward DM, Langelier C, et al. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007;18:2569–2578
  158. Frazer DM, Wilkins SJ, Becker EM, et al. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology. 2002;123:835–844
  159. Babitt JL, Huang FW, Xia Y, et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117:1933–1939
  160. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108:3204–3209
  161. Verga Falzacappa MV, Vujic Spasic M, Kessler R, et al. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109:353–358
  162. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–539
  163. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36:77–82
  164. Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood. 2005;106:2884–2889
  165. Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2:399–409
  166. Lin L, Valore EV, Nemeth E, et al. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood. 2007;110:2182–2189
  167. Zhang AS, Anderson SA, Meyers KR, et al. Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem. 2007;282:12547–12556
  168. Silvestri L, Pagani A, Camaschella C. Furin mediated release of soluble hemojuvelin: A new link between hypoxia and iron homeostasis. Blood. 2007;
  169. 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;13:399–408
  170. Waheed A, Parkkila S, Saarnio J, et al. Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proc Natl Acad Sci U S A. 1999;96:1579–1584
  171. West AR, Thomas C, Sadlier J, et al. Haemochromatosis protein is expressed on the terminal web of enterocytes in proximal small intestine of the rat. Histochem Cell Biol. 2006;125:283–292
  172. Sebastiani G, Walker AP. HFE Gene in primary and secondary hepatic iron overload. World J Gastroenterol. 2007;13:4673–4689
  173. Lebron JA, Bennett MJ, Vaughn DE, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998;93:111–123
  174. Feder JN, Tsuchihashi Z, Irrinki A, et al. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem. 1997;272:14025–14028
  175. Parkkila S, Waheed A, Britton RS, et al. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci U S A. 1997;94:13198–13202
  176. Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A. 1998;95:1472–1477
  177. Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281:28494–28498
  178. West AP, Giannetti AM, Herr AB, et al. Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites. J Mol Biol. 2001;313:385–397
  179. Waheed A, Grubb JH, Zhou XY, et al. Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci U S A. 2002;99:3117–3122
  180. Fleming RE, Sly WS. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol. 2002;64:663–680
  181. Calzolari A, Raggi C, Deaglio S, et al. TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. J Cell Sci. 2006;119:4486–4498
  182. Chua AC, Graham RM, Trinder D, et al. The regulation of cellular iron metabolism. Crit Rev Clin Lab Sci. 2007;44:413–459
  183. Arredondo M, Tapia V, Rojas A, et al. Apical distribution of HFE-beta2-microglobulin is associated with inhibition of apical iron uptake in intestinal epithelia cells. Biometals. 2006;19:379–388
  184. Lam-Yuk-Tseung S, Camaschella C, Iolascon A, et al. A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload. Blood Cells Mol Dis. 2006;36:347–354
  185. Iolascon A, d'Apolito M, Servedio V, et al. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood. 2006;107:349–354
  186. Beaumont C, Delaunay J, Hetet G, et al. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood. 2006;107:4168–4170
  187. Lam-Yuk-Tseung S, Mathieu M, Gros P. Functional characterization of the E399D DMT1/NRAMP2/SLC11A2 protein produced by an exon 12 mutation in a patient with microcytic anemia and iron overload. Blood Cells Mol Dis. 2005;35:212–216
  188. Zhao R, Min SH, Qiu A, et al. The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood. 2007;110:1147–1152
  189. Robson KJ, Merryweather-Clarke AT, Cadet E, et al. Recent advances in understanding haemochromatosis: A transition state. J Med Genet. 2004;41:721–730
  190. De Domenico I, McVey Ward D, Nemeth E, et al. Molecular and clinical correlates in iron overload associated with mutations in ferroportin. Haematologica. 2006;91:1092–1095
  191. De Domenico I, Ward DM, Musci G, et al. Evidence for the multimeric structure of ferroportin. Blood. 2007;109:2205–2209
  192. Vassiliev V, Harris ZL, Zatta P. Ceruloplasmin in neurodegenerative diseases. Brain Res Brain Res Rev. 2005;49:633–640
  193. Miyajima H. Aceruloplasminemia, an iron metabolic disorder. Neuropathology. 2003;23:345–350
  194. Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med. 1996;335:1169–1175
  195. Baron M, Kudin AP, Kunz WS. Mitochondrial dysfunction in neurodegenerative disorders. Biochem Soc Trans. 2007;35:1228–1231
  196. Krasilnikova MM, Kireeva ML, Petrovic V, et al. Effects of Friedreich's ataxia (GAA)n⁎(TTC)n repeats on RNA synthesis and stability. Nucleic Acids Res. 2007;35:1075–1084
  197. Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271:1423–1427
  198. Wilson RB. Iron dysregulation in Friedreich ataxia. Semin Pediatr Neurol. 2006;13:166–175
  199. Yang M, Cobine PA, Molik S, et al. The effects of mitochondrial iron homeostasis on cofactor specificity of superoxide dismutase 2. EMBO J. 2006;25:1775–1783
  200. Martelli A, Wattenhofer-Donze M, Schmucker S, et al. Frataxin is essential for extramitochondrial Fe S cluster proteins in mammalian tissues. Hum Mol Genet. 2007;16:2651–2658
  201. Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci. 2001;2:492–501
  202. Spillantini MG, Crowther RA, Jakes R, et al. Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A. 1998;95:6469–6473
  203. Bharathi , Indi SS, Rao KS. Copper- and iron-induced differential fibril formation in alpha-synuclein: TEM study. Neurosci Lett. 2007;424:78–82
  204. Friedlich AL, Tanzi RE, Rogers JT. The 5′-untranslated region of Parkinson's disease alpha-synuclein messenger RNA contains a predicted iron responsive element. Mol Psychiatry. 2007;12:222–223
  205. Kaur D, Andersen JK. Ironing out Parkinson's disease: Is therapeutic treatment with iron chelators a real possibility?. Aging Cell. 2002;1:17–21
  206. Ostrerova-Golts N, Petrucelli L, Hardy J, et al. The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci. 2000;20:6048–6054
  207. Atwood CS, Obrenovich ME, Liu T, et al. Amyloid-beta: A chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev. 2003;43:1–16
  208. 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;277:45518–45528
  209. Bush AI. The metallobiology of Alzheimer's disease. Trends Neurosci. 2003;26:207–214
  210. Atamna H. Heme binding to amyloid-beta peptide: Mechanistic role in Alzheimer's disease. J Alzheimers Dis. 2006;10:255–266
  211. Smith DG, Cappai R, Barnham KJ. The redox chemistry of the Alzheimer's disease amyloid beta peptide. Biochim Biophys Acta. 2007;1768:1976–1990
  212. Curtis AR, Fey C, Morris CM, et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet. 2001;28:350–354
  213. Vidal R, Ghetti B, Takao M, et al. Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene. J Neuropathol Exp Neurol. 2004;63:363–380
  214. Burn J, Chinnery PF. Neuroferritinopathy. Semin Pediatr Neurol. 2006;13:176–181
  215. Cremonesi L, Foglieni B, Fermo I, et al. Identification of two novel mutations in the 5′-untranslated region of H-ferritin using denaturing high performance liquid chromatography scanning. Haematologica. 2003;88:1110–1116

 This study was supported in part by a grant from the Canadian Blood Services–Canadian Institutes of Health Research (CIHR) Program in Blood Utilization and Conservation awarded to RTAM. MRB was supported by a graduate studentship from the Strategic Training Program in Transfusion Science (funded by the CIHR and the Heart and Stroke Foundation of Canada). AYKW was supported by a graduate studentship from CBS.

PII: S0887-7963(08)00104-1

doi: 10.1016/j.tmrv.2008.12.001

Transfusion Medicine Reviews
Volume 23, Issue 2 , Pages 103-123 , April 2009