Pediatric Neurology
Volume 25, Issue 2 , Pages 130-137 , August 2001

Systemic iron metabolism: a review and implications for brain iron metabolism

  • Tracey A Rouault, MD

      Affiliations

    • Section on Human Iron Metabolism; Cell Biology and Metabolism Branch; National Institute of Child Health and Human Disease; Bethesda, Maryland, USA
    • Corresponding Author InformationCommunications should be addressed to: Dr. Rouault; Section on Human Iron Metabolism; Cell Biology and Metabolism Branch; National Institute of Child Health and Human Disease; Bethesda, MD 20892

Received 26 September 2000 ,Accepted 5 February 2001.

References 

  1. Koppenol WH. The centennial of the Fenton reaction. Free Radic Biol Med. 1993;15:645–651
  2. Rouault T, Klausner R. Regulation of iron metabolism in eukaryotes. Curr Top Cell Regul. 1997;35:1–19
  3. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341:1986–1995
  4. Bothwell TH. Overview and mechanisms of iron regulation. Nutr Rev. 1995;53:237–245
  5. Santos M, Wienk KJ, Schilham MW, Clevers H, de Sousa M, Marx JJ. In vivo mucosal uptake, mucosal transfer and retention of iron in mice. Lab Anim. 1997;31:264–270
  6. McLaren GD, Nathanson MH, Jacobs A, Trevett D, Thomson W. Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis. J Lab Clin Med. 1991;117:390–401
  7. Andrews NC, Fleming MD, Gunshin H. Iron transport across biologic membranes. Nutr Rev. 1999;57:114–123
  8. Gunshin H, Mackenzie B, Berger UV, et al.  Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482–488
  9. Canonne-Hergaux F, Gruenheid S, Ponka P, Gros P. Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood. 1999;93:4406–4417
  10. Fleming MD, Trenor CCR, Su MA, et al.  Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16:383–386
  11. Picard V, Govoni G, Jabado N, Gros P. NRAMP 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein accessible cytoplasmic pool. J Biol Chem. 2000;275:35738–35745
  12. Trinder D, Oates PS, Thomas C, Sadleir J, Morgan EH. Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload. Gut. 2000;46:270–276
  13. Donovan A, Brownlie A, Zhou Y, et al.  Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403:776–781
  14. 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
  15. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275:19906–19912
  16. 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
  17. Gitlin JD. Aceruloplasminemia. Pediatr Res. 1998;44:271–276
  18. Aisen P. Iron metabolism (An evolutionary perspective). In:  Brock J,  Halliday JH,  Pippard MJ,  Powell LW editor. Iron metabolism in health and disease. Philadelphia: WB Saunders; 1994;p. 1–30
  19. Baker E, Morgan EH. Iron transport. In:  Brock J,  Halliday JH,  Pippard MJ,  Powell LW editor. Iron metabolism in health and disease. Philadelphia: WB Saunders; 1994;p. 63–95
  20. Odorizzi G, Trowbridge IS. Structural requirements for basolateral sorting of the human transferrin receptor in the biosynthetic and endocytic pathways of Madin-Darby canine kidney cells. J Cell Biol. 1997;137:1255–1264
  21. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. Nramp2 is mutated in the anemic Belgrade (b) rat (Evidence of a role for Nramp2 in endosomal iron transport). Proc Natl Acad Sci USA. 1998;95:1148–1153
  22. Theil EC. Ferritins. Annu Rev Biochem. 1987;56:289–315
  23. Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol. 1998;35:35–54
  24. Brittenham GB. In:  Brock JH,  Halliday JW,  Pippard MJ,  Powell LW editor. The red cell cycle. Iron metabolism in health and disease. Philadelphia: WB Saunders; 1994;p. 31–62
  25. Maines MD. The heme oxygenase system and its functions in the brain. Cell Mol Biol (Noisy-Le-Grand). 2000;46:573–585
  26. Moura E, Noordermeer MA, Verhoeven N, Verheul AF, Marx JJ. Iron release from human monocytes after erythrophagocytosis in vitro (An investigation in normal subjects and hereditary hemochromatosis patients). Blood. 1998;92:2511–2519
  27. Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA. 1997;94:10919–10924
  28. Klomp LW, Farhangrazi ZS, Dugan LL, Gitlin JD. Ceruloplasmin gene expression in the murine central nervous system. J Clin Invest. 1996;98:207–215
  29. 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 USA. 1996;93:8175–8182
  30. Gruer MJ, Artymiuk PJ, Guest JR. The aconitase family (Three structural variations on a common theme). Trends Biochem Sci. 1997;22:3–6
  31. Addess KJ, Basilion JP, Klausner RD, Rouault TA, Pardi AJ. Structure and dynamics of the iron responsive element RNA (Implications for binding of the RNA by iron regulatory proteins). J Mol Biol. 1997;274:72–83
  32. Gdaniec Z, Sierzputowska-Gracz H, Theil EC. Iron regulatory element and internal loop/bulge structure for ferritin mRNA studied by cobalt (III) hexammine binding, molecular modeling, and NMR spectroscopy. Biochemistry. 1998;37:1505–1512
  33. Allerson CR, Cazzola M, Rouault TA. Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome. J Biol Chem. 1999;274:26439–26447
  34. Butt J, Kim HY, Basilion JP, et al.  Differences in the RNA binding sites of iron regulatory proteins and potential target diversity. Proc Natl Acad Sci USA. 1996;93:4345–4349
  35. Gray NK, Hentze MW. Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs. EMBO J. 1994;13:3882–3891
  36. Binder R, Horowitz JA, Basilion JP, Koeller DM, Klausner RD, Harford JB. Evidence that the pathway of transferrin receptor mRNA degradation involves an endonucleolytic cleavage within the 3′UTR and does not involve poly(A) tail shortening. EMBO J. 1994;13:1969–1980
  37. Beinert H, Holm RH, Munck E. Iron-sulfur clusters (Nature’s modular, multipurpose structures). Science. 1997;277:653–659
  38. Zheng L, Cash VL, Flint DH, Dean DR. Assembly of iron-sulfur clusters. Identification of an iscSUA-hscBA-fdx gene cluster from Azotobacter vinelandii. J Biol Chem. 1998;273:13264–13272
  39. Strain J, Lorenz CR, Bode J, et al.  Suppressors of superoxide dismutase (SOD1) deficiency in Saccharomyces cerevisiae. Identification of proteins predicted to mediate iron-sulfur cluster assembly. J Biol Chem. 1998;273:31138–31144
  40. Land T, Rouault TA. Targeting of a human iron-sulfur cluster assembly enzyme, nifs, to different subcellular compartments is regulated through alternative AUG utilization. Mol Cell. 1998;2:807–815
  41. Tong WH, Rouault T. Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. EMBO J. 2000;19:5692–5700
  42. Rouault TA, Klausner RD. Iron-sulfur clusters as biosensors of oxidants and iron. Trends Biochem Sci. 1996;21:174–177
  43. Beinert H, Kiley P. Redox control of gene expression involving iron-sulfur proteins. Change of oxidation-state or assembly/disassembly of Fe-S clusters?. FEBS Lett. 1996;382:218–221
  44. Pantopoulos K, Hentze MWF. Rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J. 1995;14:2917–2924
  45. Tang CK, Chin J, Harford JB, Klausner RD, Rouault TA. Iron regulates the activity of the iron-responsive element binding protein without changing its rate of synthesis or degradation. J Biol Chem. 1992;267:24466–24470
  46. Oliveira L, Drapier JC. Down-regulation of iron regulatory protein 1 gene expression by nitric oxide. Proc Natl Acad Sci USA. 2000;97:6550–6555
  47. Guo B, Phillips JD, Yu Y, Leibold EA. Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem. 1995;270:21645–21651
  48. Iwai K, Klausner RD, Rouault TA. Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2. EMBO J. 1995;14:5350–5357
  49. Iwai K, Drake SK, Wehr NB, et al.  Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2 (Implications for degradation of oxidized proteins). Proc Natl Acad Sci USA. 1998;95:4924–4928
  50. Samaniego F, Chin J, Iwai K, Rouault TA, Klausner RD. Molecular characterization of a second iron responsive element binding protein, iron regulatory protein 2 (IRP2) (Structure, function and post-translational regulation). J Biol Chem. 1994;269:30904–30910
  51. Wu KJ, Polack A, Dalla-Favera R. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science. 1999;283:676–679
  52. Jordan A, Reichard P. Ribonucleotide reductases. Ann Rev Biochem. 1998;67:71–98
  53. Henderson BR, Menotti E, Kuhn LC. Iron regulatory proteins 1 and 2 bind distinct sets of RNA target sequences. J Biol Chem. 1996;271:4900–4908
  54. Menotti E, Henderson BR, Kuhn LC. Translational regulation of mRNAs with distinct IRE sequences by iron regulatory proteins 1 and 2. J Biol Chem. 1998;273:1821–1824
  55. Hanson ES, Leibold EA. Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species. Gene Expr. 1999;7:367–376
  56. Bradbury MW. Transport of iron in the blood-brain-cerebrospinal fluid system. J Neurochem. 1997;69:443–454
  57. Holash JA, Harik SI, Perry G, Stewart PA. Barrier properties of testis microvessels. Proc Natl Acad Sci USA. 1993;90:11069–11073
  58. Kennedy ML, Douglas GC, King BF. Effect of iron on transferrin receptor expression by human placental syncytiotrophoblast cells. Reprod Fertil Dev. 1997;9:609–616
  59. 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 USA. 1999;96:1579–1584
  60. LaVaute T, Smith S, Cooperman S, et al.  Targeted deletion of iron regulatory protein 2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001;27:209–214
  61. Swaiman KF. Hallervorden-Spatz syndrome and brain iron metabolism. Arch Neurol. 1991;48:1285–1293
  62. Puccio H, Koenig M. Recent advances in the molecular pathogenesis of Friedreich ataxia. Hum Mol Genet. 2000;9:887–892
  63. Morris CM, Candy JM, Keith AB, et al.  Brain iron homeostasis. J Inorg Biochem. 1992;47:257–265
  64. Hayashi Y, Nomura M, Yamagishi S, Harada S, Yamashita J, Yamamoto H. Induction of various blood-brain barrier properties in non-neural endothelial cells by close apposition to co-cultured astrocytes. Glia. 1997;19:13–26
  65. Moos T. Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system. J Comp Neurol. 1996;375:675–692
  66. Qian ZM, To Y, Tang PL, Feng YM. Transferrin receptors on the plasma membrane of cultured rat astrocytes. Exp Brain Res. 1999;129:473–476
  67. Crowe A, Morgan EH. Iron and transferrin uptake by brain and cerebrospinal fluid in the rat. Brain Res. 1992;592:8–16
  68. Moos T, Morgan EH. Evidence for low molecular weight, non-transferrin-bound iron in rat brain and cerebrospinal fluid. J Neurosci Res. 1998;54:486–494
  69. Patel BN, Dunn RJ, David S. Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain. J Biol Chem. 2000;275:4305–4310
  70. Hansen TM, Nielsen H, Bernth N, Moos T. Expression of ferritin protein and subunit mRNAs in normal and iron deficient rat brain. Brain Res Mol Brain Res. 1999;65:186–197
  71. Connor JR, Menzies SL. Cellular management of iron in the brain. J Neurol Sci. 1995;134(Suppl):33–44
  72. Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP. Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem. 2000;275:16618–16625
  73. Burdo JR, Martin J, Menzies SL, et al.  Cellular distribution of iron in the brain of the Belgrade rat. Neuroscience. 1999;93:1189–1196
  74. Taylor EM, Crowe A, Morgan EH. Transferrin and iron uptake by the brain (Effects of altered iron status). J Neurochem. 1991;57:1584–1592
  75. Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol. 2000;20:77–95
  76. van Gelder W, Huijskes-Heins MI, Cleton-Soeteman MI, van Dijk JP, van Eijk HG. Iron uptake in blood-brain barrier endothelial cells cultured in iron-depleted and iron-enriched media. J Neurochem. 1998;71:1134–1140
  77. Ueda F, Raja KB, Simpson RJ, Trowbridge IS, Bradbury MW. Rate of 59Fe uptake into brain and cerebrospinal fluid and the influence thereon of antibodies against the transferrin receptor. J Neurochem. 1993;60:106–113
  78. Rothenberger S, Food MR, Gabathuler R, et al.  Coincident expression and distribution of melanotransferrin and transferrin receptor in human brain capillary endothelium. Brain Res. 1996;712:117–121
  79. Qian ZM, Wang Q. Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders. Brain Res Mol Brain Res Rev. 1998;27:257–267
  80. Loreal O, Gosriwatana I, Guyader D, Porter J, Brissot P, Hider RC. Determination of non-transferrin-bound iron in genetic hemochromatosis using a new HPLC-based method. J Hepatol. 2000;32:727–733
  81. Hulet SW, Heyliger SO, Powers S, Connor JR. Oligodendrocyte progenitor cells internalize ferritin via clathrin-dependent receptor mediated endocytosis. J Neurosci Res. 2000;61:52–60
  82. Moos T, Morgan EH. Kinetics and distribution of [59Fe-125I]transferrin injected into the ventricular system of the rat. Brain Res. 1998;790:115–128
  83. Qian ZM, Liao QK, To Y, et al.  Transferrin-bound and transferrin free iron uptake by cultured rat astrocytes. Cell Mol Biol (Noisy-Le-Grand). 2000;46:541–548
  84. Rouach N, Glowinski J, Giaume C. Activity-dependent neuronal control of gap-junctional communication in astrocytes. J Cell Biol. 2000;149:1513–1526
  85. Takeda A, Devenyi A, Connor JR. Evidence for non-transferrin-mediated uptake and release of iron and manganese in glial cell cultures from hypotransferrinemic mice. J Neurosci Res. 1998;51:454–462
  86. Dwork AJ, Lawler G, Zybert PA, et al.  An autoradiographic study of the uptake and distribution of iron by the brain of the young rat. Brain Res. 1990;518:31–39
  87. Sloot WN, Gramsbergen JB. Axonal transport of manganese and its relevance to selective neurotoxicity in the rat basal ganglia. Brain Res. 1994;657:124–132
  88. Pautler RG, Silva AC, Koretsky AP. In vivo neuronal tract tracing using manganese-enhanced magnetic resonance imaging. Magn Reson Med. 1998;40:740–748
  89. Fillebeen C, Descamps L, Dehouck MP, et al.  Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J Biol Chem. 1999;274:7011–7017
  90. Bastin JM, Jones M, O’Callaghan CA, Schimanski L, Mason DY, Townsend AR. Kupffer cell staining by an HFE-specific monoclonal antibody (implications for hereditary haemochromatosis). Br J Haematol. 1998;103:931–941
  91. Dwork AJ. Effects of diet and development upon the uptake and distribution of cerebral iron. J Neurol Sci. 1995;134(Suppl):45–51
  92. Zhou XY, Tomatsu S, Fleming RE, et al.  HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA. 1998;95:2492–2497
  93. Levy JE, Montross LK, Cohen DE, Fleming MD, Andrews NC. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood. 1999;94:9–11
  94. 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 USA. 1999;96:10812–10817

PII: S0887-8994(01)00260-0

Pediatric Neurology
Volume 25, Issue 2 , Pages 130-137 , August 2001

Article Tools