, 20:549 | Cite as

Metabolic regulation of citrate and iron by aconitases: role of iron–sulfur cluster biogenesis

  • Wing-Hang Tong
  • Tracey A. Rouault


Iron and citrate are essential for the metabolism of most organisms, and regulation of iron and citrate biology at both the cellular and systemic levels is critical for normal physiology and survival. Mitochondrial and cytosolic aconitases catalyze the interconversion of citrate and isocitrate, and aconitase activities are affected by iron levels, oxidative stress and by the status of the Fe–S cluster biogenesis apparatus. Assembly and disassembly of Fe–S clusters is a key process not only in regulating the enzymatic activity of mitochondrial aconitase in the citric acid cycle, but also in controlling the iron sensing and RNA binding activities of cytosolic aconitase (also known as iron regulatory protein IRP1). This review discusses the central role of aconitases in intermediary metabolism and explores how iron homeostasis and Fe–S cluster biogenesis regulate the Fe–S cluster switch and modulate intracellular citrate flux.


Iron–sulfur cluster biogenesis Aconitase Citrate metabolism Iron metabolism 


  1. Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275:19906–19912PubMedCrossRefGoogle Scholar
  2. Acquaviva F, De Biase I, Nezi L et al (2005) Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2. J Cell Sci 118:3917–3924PubMedCrossRefGoogle Scholar
  3. Adam AC, Bornhovd C, Prokisch H, Neupert W, Hell K (2006) The Nfs1 interacting protein Isd11 has an essential role in Fe/S cluster biogenesis in mitochondria. EMBO J 25:174–183PubMedCrossRefGoogle Scholar
  4. Agar JN, Krebs C, Frazzon J, Huynh BH, Dean DR, Johnson MK (2000) IscU as a scaffold for iron–sulfur cluster biosynthesis: sequential assembly of [2Fe-4S] and [4Fe-4S] clusters in IscU. Biochemistry 39:7856–7862PubMedCrossRefGoogle Scholar
  5. Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, Koeller DM (1999) Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet 8:743–749PubMedCrossRefGoogle Scholar
  6. Anderson PR, Kirby K, Hilliker AJ, Phillips JP (2005) RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila. Hum Mol Genet 14:3397–3405PubMedCrossRefGoogle Scholar
  7. Armstrong JS, Whiteman M, Yang H, Jones DP (2004) The redox regulation of intermediary metabolism by a superoxide-aconitase rheostat. Bioessays 26:894–900PubMedCrossRefGoogle Scholar
  8. Babcock M, de Silva D, Oaks R et al (1997) Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 276:1709–1712PubMedCrossRefGoogle Scholar
  9. Balasubramanian R, Shen G, Bryant DA, Golbeck JH (2006) Regulatory roles for IscA and SufA in iron homeostasis and redox stress responses in the cyanobacterium Synechococcus sp. strain PCC 7002. J Bacteriol 188:3182–3191PubMedCrossRefGoogle Scholar
  10. Balk J, Aguilar Netz DJ, Tepper K, Pierik AJ, Lill R (2005) The essential WD40 protein Cia1 is involved in a late step of cytosolic and nuclear iron–sulfur protein assembly. Mol Cell Biol 25:10833–10841PubMedCrossRefGoogle Scholar
  11. Beard JL, Connor JR (2003) Iron status and neural functioning. Annu Rev Nutr 23:41–58PubMedCrossRefGoogle Scholar
  12. Beinert H, Holm RH, Munck E (1997) Iron–sulfur clusters: nature’s modular, multipurpose structures. Science 277:653–659PubMedCrossRefGoogle Scholar
  13. Beinert H, Kennedy MC, Stout CD (1996) Aconitase as iron–protein, enzyme, and iron-regulatory protein. Chem Rev 96:2335–2374PubMedCrossRefGoogle Scholar
  14. Belfiore F, Iannello S (1998) Insulin resistance in obesity: metabolic mechanisms and measurement methods. Mol Gen Metab 65:121–128CrossRefGoogle Scholar
  15. Bell JD, Brown JC, Sadler PJ et al (1987) High resolution proton nuclear magnetic resonance studies of human cerebrospinal fluid. Clin Sci (Lond). 72:563–570Google Scholar
  16. Bisaccia F, De Palma A, Palmieri F (1989) Identification and purification of the tricarboxylate carrier from rat liver mitochondria. Biochim Biophys Acta 977:171–176PubMedCrossRefGoogle Scholar
  17. Bosakowski T, Levin AA (1986) Serum citrate as a peripheral indicator of fluoroacetate and fluorocitrate toxicity in rats and dogs. Toxicol Appl Pharmacol 85:428–436PubMedCrossRefGoogle Scholar
  18. Bota DA, Davies KJ (2002) Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nat Cell Biol 4:674–680PubMedCrossRefGoogle Scholar
  19. Bouton C, Drapiers JC (2003) Iron regulatory proteins as NO signal transducers. Sci STKE 182:pe17Google Scholar
  20. Breusch FL (1937) Citric acid in tissue metabolism. Physiol Chem 250:262–280Google Scholar
  21. Bulteau AL, O’Neill HA, Kennedy MC, Ikeda-Saito M, Isaya G, Szweda LI (2004) Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science 305:242–245PubMedCrossRefGoogle Scholar
  22. Cairo G, Recalcati S, Pietrangelo A, Minotti G (2002a) The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage. Free Radic Biol Med 32:1237–1243CrossRefGoogle Scholar
  23. Cairo G, Ronchi R, Recalcati S, Campanella A, Minotti G (2002b) Nitric oxide and peroxynitrite activate the iron regulatory protein-1 of J774A.1 macrophages by direct disassembly of the Fe–S cluster of cytoplasmic aconitase. Biochemistry 41:7435–7442CrossRefGoogle Scholar
  24. Campuzano V, Montermini L, Molto M et al (1996) Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271:1423–1427PubMedCrossRefGoogle Scholar
  25. Caudarella R, Vescini F, Buffa A, Stefoni S (2003) Citrate and mineral metabolism: kidney stones and bone disease. Front Biosci 8:s1084–1106PubMedCrossRefGoogle Scholar
  26. Chen OS, Hemenway S, Kaplan J (2002) Genetic analysis of iron citrate toxicity in yeast: implications for mammalian iron homeostasis. Proc Natl Acad Sci USA 99:16922–16927PubMedCrossRefGoogle Scholar
  27. Chen OS, Schalinske KL, Eisenstein RS (1997) Dietary iron intake modulates the activity of iron regulatory proteins and the abundance of ferritin and mitochondrial aconitase in rat liver. J Nutr 127:238–248PubMedGoogle Scholar
  28. Chen XJ, Wang X, Kaufman BA, Butow RA (2005) Aconitase couples metabolic regulation to mitochondrial DNA maintenance. Science 307:714–717Google Scholar
  29. Chua AC, Olynyk JK, Leedman PJ, Trinder D (2004) Non-transferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis. Blood 104:1519–1525PubMedCrossRefGoogle Scholar
  30. Clarke SL, Vasanthakumar A, Anderson SA et al (2006) Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe–S cluster. EMBO J 25:544–553PubMedCrossRefGoogle Scholar
  31. Condo I, Ventura N, Malisan F, Tomassini B, Testi R (2006) A pool of extramitochondrial frataxin that promotes cell survival. J Biol Chem 281:16750–16756PubMedCrossRefGoogle Scholar
  32. Cooperman SS, Meyron-Holtz EG, Olivierre-Wilson H, Ghosh MC, McConnell JP, Rouault TA (2005) Microcytic anemia, erythropoietic protoporphyria and neurodegeneration in mice with targeted deletion of iron regulatory protein 2. Blood 106:1084–1091PubMedCrossRefGoogle Scholar
  33. Cossee M, Puccio H, Gansmuller A et al (2000) Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum Mol Genet 9:1219–1226PubMedCrossRefGoogle Scholar
  34. Costello LC, Franklin RB (2002) Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. Horm Metab Res 34:417–424PubMedCrossRefGoogle Scholar
  35. Costello LC, Liu Y, Franklin RB, Kennedy MC (1997) Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells. J Biol Chem 272:28875–28881PubMedCrossRefGoogle Scholar
  36. Cox TC, Bawden MJ, Martin A, May BK (1991) Human erythroid 5-aminolevulinate synthase: promoter analysis and identification of an iron-responsive element in the mRNA. EMBO J 10:1891–1902PubMedGoogle Scholar
  37. Dakubo GD, Parr RL, Costello LC, Franklin RB, Thayer RE (2006) Altered metabolism and mitochondrial genome in prostate cancer. J Clin Pathol 59:10–16PubMedCrossRefGoogle Scholar
  38. Das N, Levine RL, Orr WC, Sohal R (2001) Selectivity of protein oxidative damage during aging in Drosophila melanogaster. Biochem J 360:206–216CrossRefGoogle Scholar
  39. Delaval E, Perichon M, Friguet B (2004) Age-related impairment of mitochondrial matrix aconitase and ATP-stimulated protease in rat liver and heart. Eur J Biochem 271:4559–4564PubMedCrossRefGoogle Scholar
  40. Denton RM, Randle PJ (1966) Citrate and the regulation of adipose-tissue phosphofructokinase. Biochem J 100:420–423PubMedGoogle Scholar
  41. Donovan A, Brownlie A, Zhou Y et al (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781PubMedCrossRefGoogle Scholar
  42. Dutkiewicz R, Marszalek J, Schilke B, Craig EA, Lill R, Muhlenhoff U (2006) The Hsp70 chaperone Ssq1p is dispensable for iron–sulfur cluster formation on the scaffold protein Isu1p. J Biol Chem 281:7801–7808PubMedCrossRefGoogle Scholar
  43. Dzik WH, Kirkley SA (1988) Citrate toxicity during massive blood transfusion. Transfus Med Rev 2:76–94PubMedGoogle Scholar
  44. Fei YJ, Liu JC, Inoue K et al (2004) Relevance of NAC-2, an Na+-coupled citrate transporter, to life span, body size and fat content in Caenorhabditis elegans. Biochem J 379:191–198PubMedCrossRefGoogle Scholar
  45. Fillebeen C, Caltagirone A, Martelli A, Moulis JM, Pantopoulos K (2005) IRP1 Ser-711 is a phosphorylation site, critical for regulation of RNA-binding and aconitase activities. Biochem J 388:143–150PubMedCrossRefGoogle Scholar
  46. Fosset C, Chauveau MJ, Guillon B, Canal F, Drapier JC, Bouton C (2006) RNA silencing of mitochondrial m-Nfs1 reduces Fe–S enzyme activity both in mitochondria and cytosol of mammalian cells. J. Biol. Chem. Epub ahead of printGoogle Scholar
  47. Foury F, Talibi D (2001) Mitochondrial control of iron homeostasis. A genome wide analysis of gene expression in a yeast frataxin-deficient strain. J Biol Chem 276:7762–7768PubMedCrossRefGoogle Scholar
  48. Galy B, Ferring D, Minana B et al (2005) Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2). Blood 106:2580–2589PubMedCrossRefGoogle Scholar
  49. Ganesh S, Tsurutani N, Suzuki T et al (2003) The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain. Hum Mol Genet 12:2359–2368PubMedCrossRefGoogle Scholar
  50. Gangloff SP, Marguet D, Lauquin GJ (1990) Molecular cloning of the yeast mitochondrial aconitase gene (ACO1) and evidence of a synergistic regulation of expression by glucose plus glutamate. Mol Cell Biol 10:3551–3561PubMedGoogle Scholar
  51. Gardner PR (1997) Superoxide-driven aconitase FE–S center cycling. Biosci Rep 17:33–42PubMedCrossRefGoogle Scholar
  52. Garland SA, Hoff K, Vickery LE, Culotta VC (1999) Saccharomyces cerevisiae ISU1 and ISU2: members of a well-conserved gene family for iron–sulfur cluster assembly. J Mol Biol 294:897–907PubMedCrossRefGoogle Scholar
  53. Gerber J, Muhlenhoff U, Lill R (2003) An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1. EMBO Rep 4:906–911PubMedCrossRefGoogle Scholar
  54. Goncharov NV, Jenkins RO, Radilov AS (2006) Toxicology of fluoroacetate: a review, with possible directions for therapy research. J Appl Toxicol 26:148–161PubMedCrossRefGoogle Scholar
  55. Gourley BL, Parker SB, Jones BJ, Zumbrennen KB, Leibold EA (2003) Cytosolic aconitase and ferritin are regulated by iron in Caenorhabditis elegans. J Biol Chem 278:3227–3234PubMedCrossRefGoogle Scholar
  56. Gray NK, Pantopoulos K, Dandekar T, Ackrell BA, Hentze MW (1996) Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements. Proc Natl Acad Sci USA 93:4925–4930PubMedCrossRefGoogle Scholar
  57. Grootveld M, Bell JD, Halliwell B, Aruoma OI, Bomford A, Sadler PJ (1989) Non-transferrin bound iron in plasma or serum from patients with idiopathic hemochromatosis. J Biol Chem 264:4417–4422PubMedGoogle Scholar
  58. Gruer MJ, Artymiuk PJ, Guest JR (1997) The aconitase family: three structural variations on a common theme. Trends Biochem Sci 22:3–6Google Scholar
  59. Gunshin H, Mackenzie B, Berger UV et al (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–488PubMedCrossRefGoogle Scholar
  60. Han D, Canali R, Garcia J, Aguilera R, Gallaher TK, Cadenas E (2005) Sites and mechanisms of aconitase inactivation by peroxynitrite: modulation by citrate and glutathione. Biochemistry 44:11986–11996PubMedCrossRefGoogle Scholar
  61. Hansen JM, Go YM, Jones DP (2006) Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annu Rev Pharmacol Toxicol 46:215–234PubMedCrossRefGoogle Scholar
  62. Hanson ES, Rawlins ML, Leibold EA (2003) Oxygen and iron regulation of iron regulatory protein 2. J Biol Chem 278:40337–40342PubMedCrossRefGoogle Scholar
  63. Hentze MW, Muckenthaler MU, Andrews NC (2004) Balancing acts: molecular control of mammalian iron metabolism. Cell 117:285–297PubMedCrossRefGoogle Scholar
  64. Hertz L, Zielke HR (2004) Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci 27:735–743PubMedCrossRefGoogle Scholar
  65. Hodgkinson A (1963) The relation between citric acid and calcium metabolism with particular reference to primary hyper-parathyroidism and idiopathic hypercalciuria. Clin Sci (Lond) 24:167–178Google Scholar
  66. Huang TT, Raineri I, Eggerding F, Epstein CJ (2002) Transgenic and mutant mice for oxygen free radical studies. Methods Enzymol 349:191–213PubMedCrossRefGoogle Scholar
  67. Inoue K, Zhuang L, Maddox DM, Smith SB, Ganapathy V (2002) Structure, function, and expression pattern of a novel sodium-coupled citrate transporter (NaCT) cloned from mammalian brain. J Biol Chem 277:39469–39476PubMedCrossRefGoogle Scholar
  68. Ishikawa H, Kato M, Hori H et al (2005) Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2. Mol Cell 19:171–181PubMedCrossRefGoogle Scholar
  69. Janero DR, Hreniuk D (1996) Suppression of TCA cycle activity in the cardiac muscle cell by hydroperoxide-induced oxidative stress. Am J Physiol 270:C1735–C1742PubMedGoogle Scholar
  70. Johnson DC, Dean DR, Smith AD, Johnson MK (2005) Structure, function, and formation of biological iron-sulfur clusters. Annu Rev Biochem 74:247–281PubMedCrossRefGoogle Scholar
  71. Kaplan RS, Oliveira DL, Wilson GL (1990) Streptozotocin-induced alterations in the levels of functional mitochondrial anion transport proteins. Arch Biochem Biophys 280:181–191PubMedCrossRefGoogle Scholar
  72. Kennedy MC, Mende-Mueller L, Blondin GA, Beinert H (1992) Purification and characterization of cytosolic aconitase from beef liver and its relationship to the iron-responsive element binding protein. Proc Natl Acad Sci USA 89:11730–11734PubMedCrossRefGoogle Scholar
  73. Kim HY, Klausner RD, Rouault TA (1995) Translational repressor activity is equivalent and is quantitatively predicted by in vitro RNA binding for two iron-responsive element-binding proteins, IRP1 and IRP2. J Biol Chem 270:4983–4986PubMedCrossRefGoogle Scholar
  74. Kim HY, LaVaute T, Iwai K, Klausner RD, Rouault TA (1996) Identification of a conserved and functional iron-responsive element in the 5’-untranslated region of mammalian mitochondrial aconitase. J Biol Chem 271:24226–24230PubMedCrossRefGoogle Scholar
  75. Kim S, Ponka P (2003) Role of nitric oxide in cellular iron metabolism. Biometals 16:125–135PubMedCrossRefGoogle Scholar
  76. Knauf F, Mohebbi N, Teichert C et al (2006) The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates. Biochem J 397:25–29PubMedCrossRefGoogle Scholar
  77. Knight SA, Sepuri NB, Pain D, Dancis A (1998) Mt-Hsp70 homolog, Ssc2p, required for maturation of yeast frataxin and mitochondrial iron homeostasis. J Biol Chem 273:18389–18393PubMedCrossRefGoogle Scholar
  78. Koh HJ, Lee SM, Son BG et al (2004) Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism. J Biol Chem 279:39968–39974PubMedCrossRefGoogle Scholar
  79. Kohler SA, Henderson BR, Kuhn LC (1995) Succinate dehydrogenase b mRNA of Drosophila melanogaster has a functional iron-responsive element in its 5’-untranslated region. J Biol Chem 270:30781–30786PubMedCrossRefGoogle Scholar
  80. Konstantinova SG, Russanov EM (1996) Aconitase activity in rat liver. Comp Biochem Physiol B Biochem Mol Biol 113:125–130PubMedCrossRefGoogle Scholar
  81. Koutnikova H, Campuzano V, Foury F, Dolle P, Cazzalini O, Koenig M (1997) Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet 16:345–351PubMedCrossRefGoogle Scholar
  82. Land T, Rouault TA (1998) Targeting of a human iron–sulfur cluster assembly enzyme, nifs, to different subcellular compartments is regulated through alternative AUG utilization. Mol Cell 2:807–815PubMedCrossRefGoogle Scholar
  83. Lange H, Kaut A, Kispal G, Lill R (2000) A mitochondrial ferredoxin is essential for biogenesis of cellular iron–sulfur proteins. Proc Natl Acad Sci USA 97:1050–1055PubMedCrossRefGoogle Scholar
  84. LaNoue KF, Schoolwerth AC (1979) Metabolite transport in mitochondria. Annu Rev Biochem 48:871–922PubMedCrossRefGoogle Scholar
  85. LaVaute T, Smith S, Cooperman S et al (2001) Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet 27:209–214PubMedCrossRefGoogle Scholar
  86. Lawlis VB, Roche TE (1980) Effect of micromolar Ca2+ on NADH inhibition of bovine kidney alpha-ketoglutarate dehydrogenase complex and possible role of Ca2+ in signal amplification. Mol Cell Biochem 32:147–152PubMedCrossRefGoogle Scholar
  87. Lewis SM (2005) Introduction—the global problem of nutritional anemias. Hematology 10:224–226CrossRefGoogle Scholar
  88. Li Y, Huang TT, Carlson EJ et al (1995) Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 11:376–381PubMedCrossRefGoogle Scholar
  89. Li J, Kogan M, Knight SAB, Pain D, Dancis A (1999) Yeast mitochondrial protein, Nfs1p, coordinately regulates iron–sulfur cluster proteins, cellular iron uptake, and iron distribution. J Biol Chem 274:33025–33034PubMedCrossRefGoogle Scholar
  90. Li K, Tong WH, Hughes RM, Rouault TA (2006) Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and scaffold protein, ISCU, in iron–sulfur cluster assembly. J Biol Chem 281:12344–12351PubMedCrossRefGoogle Scholar
  91. Liew YF, Shaw NS (2005) Mitochondrial cysteine desulfurase iron–sulfur cluster S and aconitase are post-transcriptionally regulated by dietary iron in skeletal muscle of rats. J Nutr 135:2151–2158PubMedGoogle Scholar
  92. Lill R, Muhlenhoff U (2005) Iron–sulfur–protein biogenesis in eukaryotes. Trends Biochem Sci 30:133–141PubMedCrossRefGoogle Scholar
  93. Lind MI, Missirlis F, Melefors O et al (2006) Of two cytosolic aconitases expressed in Drosophila, only one functions as an iron regulatory protein. J Biol Chem 281:18707–18714PubMedCrossRefGoogle Scholar
  94. Lipinski P, Starzynski RR, Drapier JC et al (2005) Induction of iron regulatory protein 1 RNA-binding activity by nitric oxide is associated with a concomitant increase in the labile iron pool: implications for DNA damage. Biochem Biophys Res Commun 327:349–355PubMedCrossRefGoogle Scholar
  95. Lorain S, Lecluse Y, Scamps C, Mattei MG, Lipinski M (2001) Identification of human and mouse HIRA-interacting protein-5 (HIRIP5), two mammalian representatives in a family of phylogenetically conserved proteins with a role in the biogenesis of Fe/S proteins. Biochim Biophys Acta 1517:376–383PubMedGoogle Scholar
  96. Martin RB (1986) Citrate binding of Al3+ and Fe3+. J Inorg Biochem 28:181–187PubMedCrossRefGoogle Scholar
  97. McGahan MC, Harned J, Mukunnemkeril M, Goralska M, Fleisher L, Ferrell JB (2005) Iron alters glutamate secretion by regulating cytosolic aconitase activity. Am J Physiol Cell Physiol 288:C1117–C1124PubMedCrossRefGoogle Scholar
  98. McGarry JD, Mannaerts GP, Foster DW (1977) A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest 60:265–270PubMedCrossRefGoogle Scholar
  99. McKie AT, Marciani P, Rolfs A et al (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299–309PubMedCrossRefGoogle Scholar
  100. Melefors O Hentze MW (1993) Translational regulation by mRNA/protein interactions in eukaryotic cells: ferritin and beyond. Bioessays 15:85–90CrossRefGoogle Scholar
  101. Melnick JZ, Preisig PA, Moe OW, Srere P, Alpern RJ (1998) Renal cortical mitochondrial aconitase is regulated in hypo- and hypercitraturia. Kidney Int 54:160–165PubMedCrossRefGoogle Scholar
  102. Meyron-Holtz EG, Ghosh MC, Iwai K et al (2004a) Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J 23:386–395CrossRefGoogle Scholar
  103. Meyron-Holtz EG, Ghosh MC, Rouault TA (2004b) Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science 306:2087–2090CrossRefGoogle Scholar
  104. Minard KI, McAlister-Henn L (2005) Sources of NADPH in yeast vary with carbon source. J Biol Chem 280:39890–39896PubMedCrossRefGoogle Scholar
  105. Missirlis F, Hu J, Kirby K, Hilliker AJ, Rouault TA, Phillips JP (2003) Compartment-specific protection of iron–sulfur proteins by superoxide dismutase. J Biol Chem 278:47365–47369PubMedCrossRefGoogle Scholar
  106. Molina-Navarro MM, Casas C, Piedrafita L, Belli G, Herrero E (2006) Prokaryotic and eukaryotic monothiol glutaredoxins are able to perform the functions of Grx5 in the biogenesis of Fe/S clusters in yeast mitochondria. FEBS Lett 580:2273–2280PubMedCrossRefGoogle Scholar
  107. Muckenthaler M, Gunkel N, Frishman D, Cyrklaff A, Tomancak P, Hentze MW (1998) Iron-regulatory protein-1 (IRP-1) is highly conserved in two invertebrate species—characterization of IRP-1 homologues in Drosophila melanogaster and Caenorhabditis elegans. Eur J Biochem 254:230–237PubMedCrossRefGoogle Scholar
  108. Mueller S, Pantopoulos K, Hubner CA, Stremmel W, Hentze MW (2001) IRP1 activation by extracellular oxidative stress in the perfused rat liver. J Biol Chem 276:23192–23196PubMedCrossRefGoogle Scholar
  109. Mullner EW, Rothenberger S, Muller AM, Kuhn LC (1992) In vivo and in vitro modulation of the mRNA-binding activity of iron-regulatory factor. Tissue distribution and effects of cell proliferation, iron levels and redox state. Eur J Biochem 208:597–605PubMedCrossRefGoogle Scholar
  110. Munday MR (2002) Regulation of mammalian acetyl-CoA carboxylase. Biochem Soc Trans 30:1059–1064PubMedCrossRefGoogle Scholar
  111. Napier I, Ponka P, Richardson DR (2005) Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood 105:1867–1874PubMedCrossRefGoogle Scholar
  112. Napoli E, Taroni F, Cortopassi GA (2006) Frataxin, iron–sulfur clusters, heme, ROS, and aging. Antioxid Redox Signal 8:506–516PubMedCrossRefGoogle Scholar
  113. Pandolfo M (2003) Friedreich ataxia. Semin Pediatr Neurol 10:163–172PubMedCrossRefGoogle Scholar
  114. Pantopoulos K (2004) Iron metabolism and the IRE/IRP regulatory system: an update. Ann N Y Acad Sci 1012:1–13PubMedCrossRefGoogle Scholar
  115. Pantopoulos K, Hentze MW (1995) Rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J 14:2917–2924PubMedGoogle Scholar
  116. Paradies G, Ruggiero FM (1990) Enhanced activity of the tricarboxylate carrier and modification of lipids in hepatic mitochondria from hyperthyroid rats. Arch Biochem Biophys 278:425–430PubMedCrossRefGoogle Scholar
  117. Pierre JL, Gautier-Luneau I (2000) Iron and citric acid: a fuzzy chemistry of ubiquitous biological relevance. Biometals 13:91–96PubMedCrossRefGoogle Scholar
  118. Pietrangelo A (2003) Iron-induced oxidant stress in alcoholic liver fibrogenesis. Alcohol 30:121–129PubMedCrossRefGoogle Scholar
  119. Pilon M, Abdel-Ghany SE, Van Hoewyk D, Ye H, Pilon-Smits EA (2006) Biogenesis of iron–sulfur cluster proteins in plastids. Genet Eng (N Y). 27:101–117CrossRefGoogle Scholar
  120. Pondarre C, Antiochos BB, Campagna DR et al (2006) The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron–sulfur cluster biogenesis. Hum Mol Genet 15:953–964PubMedCrossRefGoogle Scholar
  121. Puig S, Askeland E, Thiele DJ (2005) Coordinated remodeling of cellular metabolism during iron deficiency through targeted mRNA degradation. Cell 120:99–110PubMedCrossRefGoogle Scholar
  122. Randle PJ (1998) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14:263–283PubMedCrossRefGoogle Scholar
  123. Regev-Rudzki N, Karniely S, Ben-Haim NN, Pines O (2005) Yeast aconitase in two locations and two metabolic pathways: seeing small amounts is believing. Mol Biol Cell 16:4163–4171PubMedCrossRefGoogle Scholar
  124. Rogina B, Reenan RA, Nilsen SP, Helfand SL (2000) Extended life-span conferred by cotransporter gene mutations in Drosophila. Science 290:2137–2140PubMedCrossRefGoogle Scholar
  125. Ross KL, Eisenstein RS (2002) Iron deficiency decreases mitochondrial aconitase abundance and citrate concentration without affecting tricarboxylic acid cycle capacity in rat liver. J Nutr 132(4):643–651PubMedGoogle Scholar
  126. Rotig A, de Lonlay P, Chretien D et al (1997) Aconitase and mitochondrial iron–sulphur protein deficiency in Friedreich ataxia. Nat Genet 17:215–217PubMedCrossRefGoogle Scholar
  127. Rouault TA, Tong WH (2005) Iron–sulphur cluster biogenesis and mitochondrial iron homeostasis. Nat Rev Mol Cell Biol 6:345–351PubMedCrossRefGoogle Scholar
  128. Rustin P, Bourgeron T, Parfait B, Chretien D, Munnich A, Rotig A (1997) Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim Biophys Acta 1361:185–197PubMedGoogle Scholar
  129. Saas J, Ziegelbauer K, von Haeseler A, Fast B, Boshart M (2000) A developmentally regulated aconitase related to iron-regulatory protein-1 is localized in the cytoplasm and in the mitochondrion of Trypanosoma brucei. J Biol Chem 275:2745–2755PubMedCrossRefGoogle Scholar
  130. Saha AK, Ruderman NB (2003) Malonyl-CoA and AMP-activated protein kinase: an expanding partnership. Mol Cell Biochem 253:65–70PubMedCrossRefGoogle Scholar
  131. Schilke B, Voisine C, Beinert H, Craig E (1999) Evidence for a conserved system for iron metabolism in the mitochondria of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 96:10206–10211PubMedCrossRefGoogle Scholar
  132. Seidler A, Jaschkowitz K, Wollenberg M (2001) Incorporation of iron–sulphur clusters in membrane-bound proteins. Biochem Soc Trans 29:418–421PubMedCrossRefGoogle Scholar
  133. Seznec H, Simon D, Monassier L et al (2004) Idebenone delays the onset of cardiac functional alteration without correction of Fe–S enzymes deficit in a mouse model for Friedreich ataxia. Hum Mol Genet 13:1017–1024PubMedCrossRefGoogle Scholar
  134. Siculella L, Sabetta S, di Summa R et al (2002) Starvation-induced posttranscriptional control of rat liver mitochondrial citrate carrier expression. Biochem Biophys Res Commun 299:418–423PubMedCrossRefGoogle Scholar
  135. Silberg JJ, Tapley TL, Hoff KG, Vickery LE (2004) Regulation of the HscA ATPase reaction cycle by the co-chaperone HscB and the iron–sulfur cluster assembly protein IscU. J Biol Chem 279:53924–53931PubMedCrossRefGoogle Scholar
  136. Singh KK, Desouki MM, Franklin RB, Costello LC (2006) Mitochondrial aconitase and citrate metabolism in malignant and non-malignant human prostate tissues. Mol Cancer 5:14PubMedCrossRefGoogle Scholar
  137. Sluse FE, Meijer AJ, Tager JM (1971) Anion translocators in rat-heart mitochondria. FEBS Lett 18:149–153PubMedCrossRefGoogle Scholar
  138. Smith AD, Agar JN, Johnson KA et al (2001) Sulfur transfer from IscS to IscU: the first step in iron–sulfur cluster biosynthesis. J Am Chem Soc 123:11103–11104PubMedCrossRefGoogle Scholar
  139. Smith SR, Cooperman S, Lavaute T et al (2004) Severity of neurodegeneration correlates with compromise of iron metabolism in mice with iron regulatory protein deficiencies. Ann N Y Acad Sci 1012:65–83PubMedCrossRefGoogle Scholar
  140. Smith SR, Ghosh MC, Ollivierre-Wilson H, Tong W-H, Rouault TA (2006) Complete loss of iron regulatory proteins 1 and 2 prevents viability of murine zygotes beyond the blastocyst stage of embryonic development. Blood Cells Mol Dis 36:283–287PubMedCrossRefGoogle Scholar
  141. Sonnewald U, Westergaard N, Krane J, Unsgard G, Petersen SB, Schousboe A (1991) First direct demonstration of preferential release of citrate from astrocytes using [13C]NMR spectroscopy of cultured neurons and astrocytes. Neurosci Lett 128:235–239PubMedCrossRefGoogle Scholar
  142. Starzynski RR, Lipinski P, Drapier J-C et al (2005) Down-regulation of iron regulatory protein 1 activities and expression in superoxide dismutase 1 knock-out mice is not associated with alterations in iron metabolism. J Biol Chem 280:4207–4212PubMedCrossRefGoogle Scholar
  143. Tong WH, Jameson GN, Huynh BH, Rouault TA (2003) Subcellular compartmentalization of human Nfu, an iron–sulfur cluster scaffold protein, and its ability to assemble a [4Fe-4S] cluster. Proc Natl Acad Sci USA 100:9762–9767PubMedCrossRefGoogle Scholar
  144. Tong W-H, Rouault T (2000) Distinct iron–sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. EMBO J 19:5692–5700PubMedCrossRefGoogle Scholar
  145. Tong WH, Rouault TA (2006) Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron–sulfur cluster biogenesis and iron homeostasis. Cell Metab 3:199–210PubMedCrossRefGoogle Scholar
  146. Tury A, Mairet-Coello G, Lisowsky T, Griffond B, Fellmann D (2005) Expression of the sulfhydryl oxidase ALR (Augmenter of Liver Regeneration) in adult rat brain. Brain Res 1048:87–97PubMedCrossRefGoogle Scholar
  147. Umbreit J (2005) Iron deficiency: a concise review. Am J Hematol 78:225–231PubMedCrossRefGoogle Scholar
  148. Urbina HD, Silberg JJ, Hoff KG, Vickery LE 2001 Transfer of sulfur from IscS to IscU during Fe/S cluster assembly. J Biol Chem 276:44521–44526PubMedCrossRefGoogle Scholar
  149. Wada M, Shimada A, Fujita T (2006) Functional characterization of Na+ -coupled citrate transporter NaC2/NaCT expressed in primary cultures of neurons from mouse cerebral cortex. Brain Res 1081:92–100PubMedCrossRefGoogle Scholar
  150. Wallace MA, Liou LL, Martins J et al (2004) Superoxide inhibits 4Fe-4S cluster enzymes involved in amino acid biosynthesis. Cross-compartment protection by CuZn-superoxide dismutase. J Biol Chem 279:32055–32062PubMedCrossRefGoogle Scholar
  151. Weinstein R (2001) Hypocalcemic toxicity and atypical reactions in therapeutic plasma exchange. J Clin Apher 16:210–211PubMedCrossRefGoogle Scholar
  152. Westergaard N, Banke T, Wahl P, Sonnewald U, Schousboe A (1995) Citrate modulates the regulation by Zn2+ of N-methyl-d-aspartate receptor-mediated channel current and neurotransmitter release. Proc Natl Acad Sci USA 92:3367–3370PubMedCrossRefGoogle Scholar
  153. Williamson JR, Cooper RH (1980) Regulation of the citric acid cycle in mammalian systems. FEBS Lett 117(Suppl):K73–K85PubMedCrossRefGoogle Scholar
  154. Wingert RA, Galloway JL, Barut B et al (2005) Deficiency of glutaredoxin 5 reveals Fe–S clusters are required for vertebrate haem synthesis. Nature 436:1035–1039PubMedCrossRefGoogle Scholar
  155. Wolfgang MJ, Lane MD (2006) Control of energy homeostasis: role of enzymes and intermediates of fatty acid metabolism in the central nervous system. Annu Rev Nutr 26:23–44 (Epub ahead of print)Google Scholar
  156. Yan L-J, Levine RL, Sohal RS (1997) Oxidative damage during aging targets mitochondrial aconitase. Proc Natl Acad Sci USA 94:11168–11172PubMedCrossRefGoogle Scholar
  157. Yang M, Cobine PA, Molik S et al (2006) The effects of mitochondrial iron homeostasis on cofactor specificity of superoxide dismutase 2. EMBO J 25:1775–1783PubMedCrossRefGoogle Scholar
  158. Yarian CS, Toroser D, Sohal RS (2006) Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice. Mech Aging Dev 127:79–84PubMedCrossRefGoogle Scholar
  159. Yoon T, Cowan JA (2003) Iron–sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe–4S] clusters in ISU-type proteins. J Am Chem Soc 125:6078–6084PubMedCrossRefGoogle Scholar
  160. Zheng L, Cash VL, Flint DH, Dean DR (1998) Assembly of iron–sulfur clusters: identification of an iscSUA-hscBA-fdx gene cluster from Azotobacter vinelandii. J Biol Chem 273:13264–13272PubMedCrossRefGoogle Scholar
  161. Zheng L, White RH, Cash VL, Jack RF, Dean DR (1993) Cysteine desulfurase activity indicates a role for NIFS in metallocluster biosynthesis. Proc Natl Acad Sci USA 90:2754–2758PubMedCrossRefGoogle Scholar
  162. Zoller H, Decristoforo C, Weiss G (2002) Erythroid 5-aminolevulinate synthase, ferrochelatase and DMT1 expression in erythroid progenitors: differential pathways for erythropoietin and iron-dependent regulation. Br J Haematol 118:619–626PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Cell Biology and Metabolism BranchNational Institute of Child Health and Human DevelopmentBethesdaUSA

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