Fixing frataxin: 'Ironing out' the metabolic defect in Friedreich's ataxia

British Journal of Pharmacology

Volumn 171, Issue 8, 2014, Pages 2174-2190

  Anzovino, A ^a   Lane, D J R ^a   Huang, M L H ^a   Richardson, D R ^a  

^a UNIVERSITY OF SYDNEY   (Australia)

Author keywords

autophagy; cardio and neurodegeneration; frataxin; Friedreich's ataxia; mitochondrial iron accumulation; oxidative stress

Indexed keywords

CHAPERONE; FERRITIN; FRATAXIN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; IRON; IRON REGULATORY PROTEIN 1; RNA BINDING PROTEIN; TRANSITION ELEMENT; IRON BINDING PROTEIN;

ANTIOXIDANT ACTIVITY; BINDING SITE; CELL METABOLISM; ENDOCYTOSIS; FRIEDREICH ATAXIA; HEME SYNTHESIS; HUMAN; INBORN ERROR OF METABOLISM; IRON CHELATION; IRON METABOLISM; IRON STORAGE; IRON TRANSPORT; MITOCHONDRIAL MEMBRANE; MOUSE; NONHUMAN; OXIDATION REDUCTION STATE; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; BIOLOGICAL MODEL; HOMEOSTASIS; METABOLISM; MITOCHONDRION; MOLECULARLY TARGETED THERAPY; PATHOPHYSIOLOGY; PHYSIOLOGY; PROCEDURES;

FRIEDREICH ATAXIA; HOMEOSTASIS; HUMANS; IRON; IRON-BINDING PROTEINS; MITOCHONDRIA; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY;

EID: 84897388919     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12470     Document Type: Review

References (179)

1. Adamec J, Rusnak F, Owen WG, Naylor S, Benson LM, Gacy AM, et al. (2000). Iron-dependent self-assembly of recombinant yeast frataxin: implications for Friedreich ataxia. Am J Hum Genet 67: 549-562.
2. Adinolfi S, Trifuoggi M, Politou AS, Martin S, Pastore A, (2002). A structural approach to understanding the iron-binding properties of phylogenetically different frataxins. Hum Mol Genet 11: 1865-1877.
3. Adinolfi S, Iannuzzi C, Prischi F, Pastore C, Iametti S, Martin SR, et al. (2009). Bacterial frataxin cyay is the gatekeeper of iron-sulfur cluster formation catalyzed by iscs. Nat Struct Mol Biol 16: 390-396.
4. Aisen P, Brown EB, (1977). The iron-binding function of transferrin in iron metabolism. Semin Hematol 14: 31-53.
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: 743-749.
6. Alper G, Narayanan V, (2003). Friedreich's ataxia. Pediatr Neurol 28: 335-341.
7. Anderson CP, Shen M, Eisenstein RS, Leibold EA, (2012). Mammalian iron metabolism and its control by iron regulatory proteins. Biochim Biophys Acta 1823: 1468-1483.
8. Andrews NC, (1999). The iron transporter dmt1. Int J Biochem Cell Biol 31: 991-994.
9. Armstrong JS, Khdour O, Hecht SM, (2010). Does oxidative stress contribute to the pathology of Friedreich's ataxia? A radical question. FASEB J 24: 2152-2163.
10. Artuch R, Aracil A, Mas A, Colome C, Rissech M, Monros E, et al. (2002). Friedreich's ataxia: idebenone treatment in early stage patients. Neuropediatrics 33: 190-193.
11. Asano T, Komatsu M, Yamaguchi-Iwai Y, Ishikawa F, Mizushima N, Iwai K, (2011). Distinct mechanisms of ferritin delivery to lysosomes in iron-depleted and iron-replete cells. Mol Cell Biol 31: 2040-2052.
12. Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, et al. (1997). Regulation of mitochondrial iron accumulation by yfh1p, a putative homolog of frataxin. Science 276: 1709-1712.
13. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY, (2007). Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 117: 1933-1939.
14. Bayot A, Santos R, Camadro JM, Rustin P, (2011). Friedreich's ataxia: the vicious circle hypothesis revisited. BMC Med 9: 112.
15. Bayot A, Reichman S, Lebon S, Csaba Z, Aubry L, Sterkers G, et al. (2013). Cis-silencing of pip5k1b evidenced in Friedreich's ataxia patient cells results in cytoskeleton anomalies. Hum Mol Genet 22: 2894-2904.
16. Becker EM, Greer JM, Ponka P, Richardson DR, (2002). Erythroid differentiation and protoporphyrin ix down-regulate frataxin expression in friend cells: characterization of frataxin expression compared to molecules involved in iron metabolism and hemoglobinization. Blood 99: 3813-3822.
17. Bencze KZ, Yoon T, Millan-Pacheco C, Bradley PB, Pastor N, Cowan JA, et al. (2007). Human frataxin: iron and ferrochelatase binding surface. Chem Commun (Cambridge, UK) 18: 1798-1800.
18. Bergsteinsdottir K, Kingston A, Mirsky R, Jessen KR, (1991). Rat schwann cells produce interleukin-1. J Neuroimmunol 34: 15-23.
19. Boddaert N, Le Quan Sang KH, Rotig A, Leroy-Willig A, Gallet S, Brunelle F, et al. (2007). Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood 110: 401-408.
20. Bou-Abdallah F, Santambrogio P, Levi S, Arosio P, Chasteen ND, (2005). Unique iron binding and oxidation properties of human mitochondrial ferritin: a comparative analysis with human h-chain ferritin. J Mol Biol 347: 543-554.
21. Camaschella C, (2009). Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment. Semin Hematol 46: 371-377.
22. Campanella A, Isaya G, O'Neill HA, Santambrogio P, Cozzi A, Arosio P, et al. (2004). The expression of human mitochondrial ferritin rescues respiratory function in frataxin-deficient yeast. Hum Mol Genet 13: 2279-2288.
23. Campanella A, Rovelli E, Santambrogio P, Cozzi A, Taroni F, Levi S, (2009). Mitochondrial ferritin limits oxidative damage regulating mitochondrial iron availability: hypothesis for a protective role in Friedreich ataxia. Hum Mol Genet 18: 1-11.
24. Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, et al. (1997). Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 6: 1771-1780.
25. Casey JL, Hentze MW, Koeller DM, Caughman SW, Rouault TA, Klausner RD, et al. (1988). Iron-responsive elements: regulatory rna sequences that control mrna levels and translation. Science 240: 924-928.
26. Cavadini P, O'Neill HA, Benada O, Isaya G, (2002). Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Hum Mol Genet 11: 217-227.
27. Cazzola M, Invernizzi R, Bergamaschi G, Levi S, Corsi B, Travaglino E, et al. (2003). Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Blood 101: 1996-2000.
28. 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: 238-248.
29. Chen OS, Hemenway S, Kaplan J, (2002). Inhibition of fe-s cluster biosynthesis decreases mitochondrial iron export: evidence that yfh1p affects fe-s cluster synthesis. Proc Natl Acad Sci U S A 99: 12321-12326.
30. Chodaczek G, Saavedra-Molina A, Bacsi A, Kruzel ML, Sur S, Boldogh I, (2007). Iron-mediated dismutation of superoxide anion augments antigen-induced allergic inflammation: effect of lactoferrin. Postepy Hig Med Dosw (Online) 61: 268-276.
31. Ciechanover A, Schwartz AL, Lodish HF, (1983). Sorting and recycling of cell surface receptors and endocytosed ligands: the asialoglycoprotein and transferrin receptors. J Cell Biochem 23: 107-130.
32. Colin F, Martelli A, Clemancey M, Latour JM, Gambarelli S, Zeppieri L, et al. (2013). Mammalian frataxin controls sulfur production and iron entry during de novo fe4s4 cluster assembly. J Am Chem Soc 135: 733-740.
33. Corsi B, Cozzi A, Arosio P, Drysdale J, Santambrogio P, Campanella A, et al. (2002). Human mitochondrial ferritin expressed in hela cells incorporates iron and affects cellular iron metabolism. J Biol Chem 277: 22430-22437.
34. Crichton RR, Dexter DT, Ward RJ, (2011). Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm 118: 301-314.
35. D'Oria V, Petrini S, Travaglini L, Priori C, Piermarini E, Petrillo S, et al. (2013). Frataxin deficiency leads to reduced expression and impaired translocation of nf-e2-related factor (nrf2) in cultured motor neurons. Int J Mol Sci 14: 7853-7865.
36. Dautry-Varsat A, Ciechanover A, Lodish HF, (1983). Ph and the recycling of transferrin during receptor-mediated endocytosis. Proc Natl Acad Sci U S A 80: 2258-2262.
37. Dhe-Paganon S, Shigeta R, Chi YI, Ristow M, Shoelson SE, (2000). Crystal structure of human frataxin. J Biol Chem 275: 30753-30756.
38. Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, et al. (2000). Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403: 776-781.
39. Drysdale J, Arosio P, Invernizzi R, Cazzola M, Volz A, Corsi B, et al. (2002). Mitochondrial ferritin: a new player in iron metabolism. Blood Cells Mol Dis 29: 376-383.
40. Eaton JW, Qian M, (2002). Molecular bases of cellular iron toxicity. Free Radic Biol Med 32: 833-840.
41. Erb M, Hoffmann-Enger B, Deppe H, Soeberdt M, Haefeli RH, Rummey C, et al. (2012). Features of idebenone and related short-chain quinones that rescue atp levels under conditions of impaired mitochondrial complex i. PLoS ONE 7: e36153.
42. Ferreira GC, Franco R, Lloyd SG, Moura I, Moura JJ, Huynh BH, (1995). Structure and function of ferrochelatase. J Bioenerg Biomembr 27: 221-229.
43. Fleming MD, Trenor CC, 3rd, Su MA, Foernzler D, Beier DR, Dietrich WF, et al. (1997). Microcytic anaemia mice have a mutation in nramp2, a candidate iron transporter gene. Nat Genet 16: 383-386.
44. Foury F, Roganti T, (2002). Deletion of the mitochondrial carrier genes mrs3 and mrs4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J Biol Chem 277: 24475-24483.
45. Foury F, Pastore A, Trincal M, (2007). Acidic residues of yeast frataxin have an essential role in fe-s cluster assembly. EMBO Rep 8: 194-199.
46. Frazzon J, Dean DR, (2003). Formation of iron-sulfur clusters in bacteria: an emerging field in bioinorganic chemistry. Curr Opin Chem Biol 7: 166-173.
47. Gakh O, Park S, Liu G, Macomber L, Imlay JA, Ferreira GC, et al. (2006). Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. Hum Mol Genet 15: 467-479.
48. Galy B, Ferring-Appel D, Sauer SW, Kaden S, Lyoumi S, Puy H, et al. (2010). Iron regulatory proteins secure mitochondrial iron sufficiency and function. Cell Metab 12: 194-201.
49. Gomez-Sarosi LA, Strasberg-Rieber M, Rieber M, (2010). H(2)o(2) preferentially synergizes with nitroprusside to induce apoptosis associated with superoxide dismutase dysregulation in human melanoma irrespective of p53 status: antagonism by o-phenanthroline. Chem Biol Interact 188: 134-143.
50. Goncalves S, Paupe V, Dassa EP, Rustin P, (2008). Deferiprone targets aconitase: implication for Friedreich's ataxia treatment. BMC Neurol 8: 20.
51. Grebien F, Kerenyi MA, Kovacic B, Kolbe T, Becker V, Dolznig H, et al. (2008). Stat5 activation enables erythropoiesis in the absence of epor and jak2. Blood 111: 4511-4522.
52. Gustafsson AB, Gottlieb RA, (2009). Autophagy in ischemic heart disease. Circ Res 104: 150-158.
53. Hejtmancik MR, Bradfield JY, Jr, Miller GV, (1949). Myocarditis and Friedreich's ataxia; a report of two cases. Am Heart J 38: 757-765.
54. Henderson BR, Kuhn LC, (1995). Differential modulation of the rna-binding proteins irp-1 and irp-2 in response to iron. Irp-2 inactivation requires translation of another protein. J Biol Chem 270: 20509-20515.
55. Hentze MW, Kuhn LC, (1996). 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 93: 8175-8182.
56. Hentze MW, Muckenthaler MU, Galy B, Camaschella C, (2010). Two to tango: regulation of mammalian iron metabolism. Cell 142: 24-38.
57. Herman D, Jenssen K, Burnett R, Soragni E, Perlman SL, Gottesfeld JM, (2006). Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat Chem Biol 2: 551-558.
58. Holley AK, Bakthavatchalu V, Velez-Roman JM, St. Clair DK, (2011). Manganese superoxide dismutase: guardian of the powerhouse. Int J Mol Sci 12: 7114-7162.
59. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC, (2005). A mouse model of juvenile hemochromatosis. J Clin Invest 115: 2187-2191.
60. Huang ML, Lane DJ, Richardson DR, (2011). Mitochondrial mayhem: the mitochondrion as a modulator of iron metabolism and its role in disease. Antioxid Redox Signal 15: 3003-3019.
61. Huang ML, Sivagurunathan S, Ting S, Jansson PJ, Austin CJ, Kelly M, et al. (2013). Molecular and functional alterations in a mouse cardiac model of Friedreich ataxia: activation of the integrated stress response, eif2alpha phosphorylation, and the induction of downstream targets. Am J Pathol 183: 745-757.
62. Huang ML-H, Becker EM, Whitnall M, Rahmanto YS, Ponka P, Richardson DR, (2009). Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant. Proc Natl Acad Sci U S A 106: 16381-16386.
63. Huynen MA, Snel B, Bork P, Gibson TJ, (2001). The phylogenetic distribution of frataxin indicates a role in iron-sulfur cluster protein assembly. Hum Mol Genet 10: 2463-2468.
64. Jacobs A, (1977). Low molecular weight intracellular iron transport compounds. Blood 50: 433-439.
65. Kakhlon O, Cabantchik ZI, (2002). The labile iron pool: characterization, measurement, and participation in cellular processes(1). Free Radic Biol Med 33: 1037-1046.
66. Kakhlon O, Manning H, Breuer W, Melamed-Book N, Lu C, Cortopassi G, et al. (2008). Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation. Blood 112: 5219-5227.
67. Kakhlon O, Breuer W, Munnich A, Cabantchik ZI, (2010). Iron redistribution as a therapeutic strategy for treating diseases of localized iron accumulation. Can J Physiol Pharmacol 88: 187-196.
68. Kaneko YS, Nakashima A, Mori K, Nagatsu T, Nagatsu I, Ota A, (2012). Microglial activation in neuroinflammation: implications for the etiology of neurodegeneration. Neurodegener Dis 10: 100-103.
69. Kearney M, Orrell RW, Fahey M, Pandolfo M, (2012). Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database Syst Rev (4): CD007791.
70. Kell DB, (2010). Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, huntington's, alzheimer's, prions, bactericides, chemical toxicology and others as examples. Arch Toxicol 84: 825-889.
71. Kerenyi MA, Grebien F, Gehart H, Schifrer M, Artaker M, Kovacic B, et al. (2008). Stat5 regulates cellular iron uptake of erythroid cells via irp-2 and tfr-1. Blood 112: 3878-3888.
72. Knaapen MW, Davies MJ, De Bie M, Haven AJ, Martinet W, Kockx MM, (2001). Apoptotic versus autophagic cell death in heart failure. Cardiovasc Res 51: 304-312.
73. Koeppen AH, (2011). Friedreich's ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci 303: 1-12.
74. Koeppen AH, Mazurkiewicz JE, (2013). Friedreich ataxia: neuropathology revised. J Neuropathol Exp Neurol 72: 78-90.
75. Koeppen AH, Michael SC, Knutson MD, Haile DJ, Qian J, Levi S, et al. (2007). The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins. Acta Neuropathol 114: 163-173.
76. Koeppen AH, Morral JA, Davis AN, Qian J, Petrocine SV, Knutson MD, et al. (2009). The dorsal root ganglion in Friedreich's ataxia. Acta Neuropathol 118: 763-776.
77. Koeppen AH, Ramirez RL, Yu D, Collins SE, Qian J, Parsons PJ, et al. (2012). Friedreich's ataxia causes redistribution of iron, copper, and zinc in the dentate nucleus. Cerebellum 11: 845-860.
78. Kubli DA, Gustafsson ÅB, (2012). Mitochondria and mitophagy: the yin and yang of cell death control. Circ Res 111: 1208-1221.
79. Lagedrost SJ, Sutton MS, Cohen MS, Satou GM, Kaufman BD, Perlman SL, et al. (2011). Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase iii study (ionia). Am Heart J 161: 639-645 e631.
80. 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: 807-815.
81. Lane DJ, Chikhani S, Richardson V, Richardson DR, (2013a). Transferrin iron uptake is stimulated by ascorbate via an intracellular reductive mechanism. Biochim Biophys Acta 1833: 1527-1541.
82. Lane DJ, Huang M, Ting S, Sivagurunathan S, Richardson DR, (2013b). Biochemistry of the cardiomyopathy in the mitochondrial disease, Friedreich's ataxia. Biochem J 453: 1-16.
83. Lane DJR, Richardson DR, (2010). Frataxin, a molecule of mystery: trading stability for function in its iron-binding site. Biochem J 426: e1-e3.
84. Lange H, Kispal G, Lill R, (1999). Mechanism of iron transport to the site of heme synthesis inside yeast mitochondria. J Biol Chem 274: 18989-18996.
85. Lawen A, Lane DJ, (2013). Mammalian iron homeostasis in health and disease: uptake, storage, transport, and molecular mechanisms of action. Antioxid Redox Signal 18: 2473-2507.
86. Leidgens S, Bullough KZ, Shi H, Li F, Shakoury-Elizeh M, Yabe T, et al. (2013). Each member of the pcbp family exhibits iron chaperone activity toward ferritin. J Biol Chem 288: 17791-17802.
87. Lesuisse E, Santos R, Matzanke BF, Knight SAB, Camadro J-M, Dancis A, (2003). Iron use for haeme synthesis is under control of the yeast frataxin homologue (yfh1). Hum Mol Genet 12: 879-889.
88. Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, et al. (2001). A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 276: 24437-24440.
89. Li H, Gakh O, Smith DY, Ranatunga WK, Isaya G, (2013). Missense mutations linked to Friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms. J Biol Chem 288: 4116-4127.
90. Lill R, (2009). Function and biogenesis of iron-sulphur proteins. Nature 460: 831-838.
91. Lill R, Hoffmann B, Molik S, Pierik AJ, Rietzschel N, Stehling O, et al. (2012). The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism. Biochim Biophys Acta 1823: 1491-1508.
92. Lin L, Goldberg YP, Ganz T, (2005). Competitive regulation of hepcidin mrna by soluble and cell-associated hemojuvelin. Blood 106: 2884-2889.
93. Lu C, Schoenfeld R, Shan Y, Tsai HJ, Hammock B, Cortopassi G, (2009). Frataxin deficiency induces schwann cell inflammation and death. Biochim Biophys Acta 1792: 1052-1061.
94. Lynch DR, Willi SM, Wilson RB, Cotticelli MG, Brigatti KW, Deutsch EC, et al. (2012). A0001 in Friedreich ataxia: biochemical characterization and effects in a clinical trial. Mov Disord 27: 1026-1033.
95. Mariotti C, Fancellu R, Caldarazzo S, Nanetti L, Di Bella D, Plumari M, et al. (2012). Erythropoietin in Friedreich ataxia: no effect on frataxin in a randomized controlled trial. Mov Disord 27: 446-449.
96. Marmolino D, Manto M, Acquaviva F, Vergara P, Ravella A, Monticelli A, et al. (2010). Pgc-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia. PLoS ONE 5: e10025.
97. Marobbio CM, Pisano I, Porcelli V, Lasorsa FM, Palmieri L, (2012). Rapamycin reduces oxidative stress in frataxin-deficient yeast cells. Mitochondrion 12: 156-161.
98. Martelli A, Wattenhofer-Donze M, Schmucker S, Bouvet S, Reutenauer L, Puccio H, (2007). Frataxin is essential for extramitochondrial fe-s cluster proteins in mammalian tissues. Hum Mol Genet 16: 2651-2658.
99. Martelli A, Napierala M, Puccio HLN, (2012). Understanding the genetic and molecular pathogenesis of Friedreich's ataxia through animal and cellular models. Dis Model Mech 5: 165-176.
100. Mathey EK, Pollard JD, Armati PJ, (1999). Tnf alpha, ifn gamma and il-2 mrna expression in cidp sural nerve biopsies. J Neurol Sci 163: 47-52.
101. Michael S, Petrocine SV, Qian J, Lamarche JB, Knutson MD, Garrick MD, et al. (2006). Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia. Cerebellum 5: 257-267.
102. Michalec L, Choudhury BK, Postlethwait E, Wild JS, Alam R, Lett-Brown M, et al. (2002). Ccl7 and cxcl10 orchestrate oxidative stress-induced neutrophilic lung inflammation. J Immunol 168: 846-852.
103. Moos T, Morgan EH, (2004). The metabolism of neuronal iron and its pathogenic role in neurological disease: review. Ann N Y Acad Sci 1012: 14-26.
104. Morgan EH, (1981). Transferrin, biochemistry, physiology and clinical significance. Mol Asp Med 4: 1-123.
105. Morgan EH, (1983). Effect of ph and iron content of transferrin on its binding to reticulocyte receptors. Biochim Biophys Acta 762: 498-502.
106. Muckenthaler MU, Galy B, Hentze MW, (2008). Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (ire/irp) regulatory network. Annu Rev Nutr 28: 197-213.
107. Munoz M, Garcia-Erce JA, Remacha AF, (2011). Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis. J Clin Pathol 64: 281-286.
108. Musco G, Stier G, Kolmerer B, Adinolfi S, Martin S, Frenkiel T, et al. (2000). Towards a structural understanding of Friedreich's ataxia: the solution structure of frataxin. Structure 8: 695-707.
109. Nandal A, Ruiz JC, Subramanian P, Ghimire-Rijal S, Sinnamon RA, Stemmler TL, et al. (2011). Activation of the hif prolyl hydroxylase by the iron chaperones pcbp1 and pcbp2. Cell Metab 14: 647-657.
110. Napier I, Ponka P, Richardson DR, (2005). Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood 105: 1867-1874.
111. Napoli E, Taroni F, Cortopassi GA, (2006). Frataxin, iron-sulfur clusters, heme, ros, and aging. Antioxid Redox Signal 8: 506-516.
112. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. (2004). Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306: 2090-2093.
113. Nie G, Sheftel AD, Kim SF, Ponka P, (2005). Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 105: 2161-2167.
114. Nunez MT, Gaete V, Watkins JA, Glass J, (1990). Mobilization of iron from endocytic vesicles. The effects of acidification and reduction. J Biol Chem 265: 6688-6692.
115. O'Neill HA, Gakh O, Park S, Cui J, Mooney SM, Sampson M, et al. (2005). Assembly of human frataxin is a mechanism for detoxifying redox-active iron. Biochemistry 44: 537-545.
116. Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, et al. (2005). Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 37: 1264-1269.
117. Ohgami RS, Campagna DR, McDonald A, Fleming MD, (2006). The steap proteins are metalloreductases. Blood 108: 1388-1394.
118. Ollinger K, Roberg K, (1997). Nutrient deprivation of cultured rat hepatocytes increases the desferrioxamine-available iron pool and augments the sensitivity to hydrogen peroxide. J Biol Chem 272: 23707-23711.
119. Palau F, Espinos C, (2006). Autosomal recessive cerebellar ataxias. Orphanet J Rare Dis 1: 47.
120. Pandolfo M, (2008). Drug insight: antioxidant therapy in inherited ataxias. Nat Clin Pract Neurol 4: 86-96.
121. Pandolfo M, (2009). Friedreich ataxia: the clinical picture. J Neurol 256: 3-8.
122. Pandolfo M, Pastore A, (2009). The pathogenesis of Friedreich ataxia and the structure and function of frataxin. J Neurol 256: 9-17.
123. Park S, Gakh O, O'Neill HA, Mangravita A, Nichol H, Ferreira GC, et al. (2003). Yeast frataxin sequentially chaperones and stores iron by coupling protein assembly with iron oxidation. J Biol Chem 278: 31340-31351.
124. Paupe V, Dassa EP, Goncalves S, Auchere F, Lonn M, Holmgren A, et al. (2009). Impaired nuclear nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS ONE 4: e4253.
125. Polonifi A, Politou M, Kalotychou V, Xiromeritis K, Tsironi M, Berdoukas V, et al. (2010). Iron metabolism gene expression in human skeletal muscle. Blood Cells Mol Dis 45: 233-237.
126. Ponka P, (1997). Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. Blood 89: 1-25.
127. Popovic Z, Templeton DM, (2004). Iron accumulation and iron-regulatory protein activity in human hepatoma (hepg2) cells. Mol Cell Biochem 265: 37-45.
128. Puccio H, Simon D, Cossee M, Criqui-Filipe P, Tiziano F, Melki J, et al. (2001). Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and fe-s enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 27: 181-186.
129. Recalcati S, Minotti G, Cairo G, (2010). Iron regulatory proteins: from molecular mechanisms to drug development. Antioxid Redox Signal 13: 1593-1616.
130. Richardson DR, (2003). Friedreich's ataxia: iron chelators that target the mitochondrion as a therapeutic strategy? Expert Opin Investig Drugs 12: 235-245.
131. Richardson DR, Ponka P, Vyoral D, (1996). Distribution of iron in reticulocytes after inhibition of heme synthesis with succinylacetone: examination of the intermediates involved in iron metabolism. Blood 87: 3477-3488.
132. Richardson DR, Lane DJR, Becker EM, Huang ML-H, Whitnall M, Rahmanto YS, et al. (2010). Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci U S A 107: 10775-10782.
133. Rotig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, et al. (1997). Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet 17: 215-217.
134. Rouault TA, (2006). The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol 2: 406-414.
135. Rouault TA, (2012). Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease. Dis Model Mech 5: 155-164.
136. Rouault TA, Tong WH, (2008). Iron-sulfur cluster biogenesis and human disease. Trends Genet 24: 398-407.
137. Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A, (1999). Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study. Lancet 354: 477-479.
138. Rustin P, Rotig A, Munnich A, Sidi D, (2002). Heart hypertrophy and function are improved by idebenone in Friedreich's ataxia. Free Radic Res 36: 467-469.
139. Sandi C, Pinto RM, Al-Mahdawi S, Ezzatizadeh V, Barnes G, Jones S, et al. (2011). Prolonged treatment with pimelic o-aminobenzamide hdac inhibitors ameliorates the disease phenotype of a Friedreich ataxia mouse model. Neurobiol Dis 42: 496-505.
140. Sandi C, Al-Mahdawi S, Pook MA, (2013). Epigenetics in Friedreich's ataxia: challenges and opportunities for therapy. Genet Res Int 2013: 852080.
141. Sano S, Inoue S, Tanabe Y, Sumiya C, Koike S, (1959). Significance of mitochondria for porphyrin and heme biosynthesis. Science 129: 275-276.
142. Santambrogio P, Biasiotto G, Sanvito F, Olivieri S, Arosio P, Levi S, (2007). Mitochondrial ferritin expression in adult mouse tissues. J Histochem Cytochem 55: 1129-1137.
143. Santambrogio P, Erba BG, Campanella A, Cozzi A, Causarano V, Cremonesi L, et al. (2011). Over-expression of mitochondrial ferritin affects the jak2/stat5 pathway in k562 cells and causes mitochondrial iron accumulation. Haematologica 96: 1424-1432.
144. Santos R, Lefevre S, Sliwa D, Seguin A, Camadro JM, Lesuisse E, (2010). Friedreich ataxia: molecular mechanisms, redox considerations, and therapeutic opportunities. Antioxid Redox Signal 13: 651-690.
145. Schalinske KL, Anderson SA, Tuazon PT, Chen OS, Kennedy MC, Eisenstein RS, (1997). The iron-sulfur cluster of iron regulatory protein 1 modulates the accessibility of rna binding and phosphorylation sites. Biochemistry 36: 3950-3958.
146. Schmucker S, Martelli A, Colin F, Page A, Wattenhofer-Donzé M, Reutenauer L, et al. (2011). Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed iscu/nfs1/isd11 iron-sulfur assembly complex. PLoS ONE 6: e16199.
147. Schmucker SP, Puccio HLN, (2010). Understanding the molecular mechanisms of Friedreich's ataxia to develop therapeutic approaches. Hum Mol Genet 19 (R1): R103-R110.
148. Seguin A, Sutak R, Bulteau AL, Garcia-Serres R, Oddou JL, Lefevre S, et al. (2010). Evidence that yeast frataxin is not an iron storage protein in vivo. Biochim Biophys Acta 1802: 531-538.
149. Seznec H, Simon D, Bouton C, Reutenauer L, Hertzog A, Golik P, et al. (2005). Friedreich ataxia: the oxidative stress paradox. Hum Mol Genet 14: 463-474.
150. Shan Y, Cortopassi G, (2012). Hsc20 interacts with frataxin and is involved in iron-sulfur cluster biogenesis and iron homeostasis. Hum Mol Genet 21: 1457-1469.
151. Shan Y, Schoenfeld RA, Hayashi G, Napoli E, Akiyama T, Iodi Carstens M, et al. (2013). Frataxin deficiency leads to defects in expression of antioxidants and nrf2 expression in dorsal root ganglia of the Friedreich's ataxia yg8r mouse model. Antioxid Redox Signal 19: 1481-1493.
152. Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, et al. (2006). Mitoferrin is essential for erythroid iron assimilation. Nature 440: 96-100.
153. Sheftel AD, Zhang AS, Brown C, Shirihai OS, Ponka P, (2007). Direct interorganellar transfer of iron from endosome to mitochondrion. Blood 110: 125-132.
154. Shi H, Bencze KZ, Stemmler TL, Philpott CC, (2008). A cytosolic iron chaperone that delivers iron to ferritin. Science 320: 1207-1210.
155. Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, et al. (2003). Coordinate regulation of glutathione biosynthesis and release by nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23: 3394-3406.
156. Shimomura H, Terasaki F, Hayashi T, Kitaura Y, Isomura T, Suma H, (2001). Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy. Jpn Circ J 65: 965-968.
157. Shvartsman M, Ioav Cabantchik Z, (2012). Intracellular iron trafficking: role of cytosolic ligands. Biometals 25: 711-723.
158. Siddappa AJ, Rao RB, Wobken JD, Casperson K, Leibold EA, Connor JR, et al. (2003). Iron deficiency alters iron regulatory protein and iron transport protein expression in the perinatal rat brain. Pediatr Res 53: 800-807.
159. Sohn YS, Breuer W, Munnich A, Cabantchik ZI, (2008). Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications. Blood 111: 1690-1699.
160. Sturm B, Bistrich U, Schranzhofer M, Sarsero JP, Rauen U, Scheiber-Mojdehkar B, et al. (2005). Friedreich's ataxia, no changes in mitochondrial labile iron in human lymphoblasts and fibroblasts: a decrease in antioxidative capacity? J Biol Chem 280: 6701-6708.
161. Theil EC, Eisenstein RS, (2000). Combinatorial mrna regulation: iron regulatory proteins and iso-iron-responsive elements (iso-ires). J Biol Chem 275: 40659-40662.
162. Tong WH, Rouault T, (2000). Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. EMBO J 19: 5692-5700.
163. Tong WH, Jameson GNL, 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 U S A 100: 9762-9767.
164. Urrutia P, Aguirre P, Esparza A, Tapia V, Mena NP, Arredondo M, et al. (2013). Inflammation alters the expression of dmt1, fpn1 and hepcidin, and it causes iron accumulation in central nervous system cells. J Neurochem 126: 541-549.
165. Wang J, Song N, Jiang H, Wang J, Xie J, (2013). Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons. Biochim Biophys Acta 1832: 618-625.
166. Wang T, Craig EA, (2008). Binding of yeast frataxin to the scaffold for fe-s cluster biogenesis, isu. J Biol Chem 283: 12674-12679.
167. Whitnall M, Rahmanto YS, Sutak R, Xu X, Becker EM, Mikhael MR, et al. (2008). The mck mouse heart model of Friedreich's ataxia: alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation. Proc Natl Acad Sci U S A 105: 9757-9762.
168. Whitnall M, Rahmanto YS, Huang ML-H, Saletta F, Lok HC, Gutiérrez L, et al. (2012). Identification of nonferritin mitochondrial iron deposits in a mouse model of Friedreich ataxia. Proc Natl Acad Sci U S A 109: 20590-20595.
169. Wingert RA, Galloway JL, Barut B, Foott H, Fraenkel P, Axe JL, et al. (2005). Deficiency of glutaredoxin 5 reveals fe-s clusters are required for vertebrate haem synthesis. Nature 436: 1035-1039.
170. Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, et al. (1999). The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet 8: 425-430.
171. Wu Y, Brosh RM, Jr, (2012). DNA helicase and helicase-nuclease enzymes with a conserved iron-sulfur cluster. Nucleic Acids Res 40: 4247-4260.
172. Wyllie JC, (1977). Transferrin uptake by rabbit alveolar macrophages in vitro. Br J Haematol 37: 17-24.
173. Yamashiro DJ, Maxfield FR, (1984). Acidification of endocytic compartments and the intracellular pathways of ligands and receptors. J Cell Biochem 26: 231-246.
174. Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, Cortopassi G, (1999). The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet 8: 425-430.
175. Ye H, Rouault TA, (2010). Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry 49: 4945-4956.
176. Yoon T, Cowan JA, (2004). Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem 279: 25943-25946.
177. Zanella I, Derosas M, Corrado M, Cocco E, Cavadini P, Biasiotto G, et al. (2008). The effects of frataxin silencing in hela cells are rescued by the
178. Zhang AS, Anderson SA, Meyers KR, Hernandez C, Eisenstein RS, Enns CA, (2007). Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem 282: 12547-12556.
179. Zou C, Hu H, Xi X, Shi Z, Wang G, Huang X, (2013). Pioglitazone protects against renal ischemia-reperfusion injury by enhancing antioxidant capacity. J Surg Res 184: 1092-1095.