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BMC Neurology
Published in: BMC Neurology 1/2008

Open Access 01-12-2008 | Research article

Deferiprone targets aconitase: Implication for Friedreich's ataxia treatment

Authors: Sergio Goncalves, Vincent Paupe, Emmanuel P Dassa, Pierre Rustin

Published in: BMC Neurology | Issue 1/2008

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Abstract

Background

Friedreich ataxia is a neurological disease originating from an iron-sulfur cluster enzyme deficiency due to impaired iron handling in the mitochondrion, aconitase being particularly affected. As a mean to counteract disease progression, it has been suggested to chelate free mitochondrial iron. Recent years have witnessed a renewed interest in this strategy because of availability of deferiprone, a chelator preferentially targeting mitochondrial iron.

Method

Control and Friedreich's ataxia patient cultured skin fibroblasts, frataxin-depleted neuroblastoma-derived cells (SK-N-AS) were studied for their response to iron chelation, with a particular attention paid to iron-sensitive aconitase activity.

Results

We found that a direct consequence of chelating mitochondrial free iron in various cell systems is a concentration and time dependent loss of aconitase activity. Impairing aconitase activity was shown to precede decreased cell proliferation.

Conclusion

We conclude that, if chelating excessive mitochondrial iron may be beneficial at some stage of the disease, great attention should be paid to not fully deplete mitochondrial iron store in order to avoid undesirable consequences.
Appendix
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Literature
1.
Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Canizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M: Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996, 271 (5254): 1423-1427. 10.1126/science.271.5254.1423.CrossRefPubMed
2.
Wilson RB: Iron dysregulation in Friedreich ataxia. Semin Pediatr Neurol. 2006, 13 (3): 166-175. 10.1016/j.spen.2006.08.005.CrossRefPubMed
3.
Rotig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P: Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997, 17 (2): 215-217. 10.1038/ng1097-215.CrossRefPubMed
4.
Tzagoloff A: Mitochondria. Cellular Organelles. Edited by: Siekevitz P. 1982, New York , Plenum Press, 1-342.
5.
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 (16): 8175-8182. 10.1073/pnas.93.16.8175.CrossRefPubMedPubMedCentral
6.
Turakhia S, Venkatakrishnan CD, Dunsmore K, Wong H, Kuppusamy P, Zweier JL, Ilangovan G: Doxorubicin-induced cardiotoxicity: direct correlation of cardiac fibroblast and H9c2 cell survival and aconitase activity with heat shock protein 27. Am J Physiol Heart Circ Physiol. 2007, 293 (5): H3111-21. 10.1152/ajpheart.00328.2007.CrossRefPubMed
7.
Chantrel-Groussard K, Geromel V, Puccio H, Koenig M, Munnich A, Rotig A, Rustin P: Disabled early recruitment of antioxidant defenses in Friedreich's ataxia. Hum Mol Genet. 2001, 10 (19): 2061-2067. 10.1093/hmg/10.19.2061.CrossRefPubMed
8.
Waldvogel D, van Gelderen P, Hallett M: Increased iron in the dentate nucleus of patients with Friedrich's ataxia. Ann Neurol. 1999, 46 (1): 123-125. 10.1002/1531-8249(199907)46:1<123::AID-ANA19>3.0.CO;2-H.CrossRefPubMed
9.
Rustin P: The use of antioxidants in Friedreich's ataxia treatment. Expert Opin Investig Drugs. 2003, 12 (4): 569-575.CrossRefPubMed
10.
Di Prospero NA, Baker A, Jeffries N, Fischbeck KH: Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 2007, 6 (10): 878-886. 10.1016/S1474-4422(07)70220-X.CrossRefPubMed
11.
Richardson DR, Mouralian C, Ponka P, Becker E: Development of potential iron chelators for the treatment of Friedreich's ataxia: ligands that mobilize mitochondrial iron. Biochim Biophys Acta. 2001, 1536 (2-3): 133-140.CrossRefPubMed
12.
Glickstein H, El RB, Shvartsman M, Cabantchik ZI: Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells. Blood. 2005, 106 (9): 3242-3250. 10.1182/blood-2005-02-0460.CrossRefPubMed
13.
Boddaert N, Le Quan Sang KH, Rotig A, Leroy-Willig A, Gallet S, Brunelle F, Sidi D, Thalabard JC, Munnich A, Cabantchik ZI: Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood. 2007, 110 (1): 401-408. 10.1182/blood-2006-12-065433.CrossRefPubMed
14.
Tong WH, Rouault TA: Metabolic regulation of citrate and iron by aconitases: role of iron-sulfur cluster biogenesis. Biometals. 2007, 20 (3-4): 549-564. 10.1007/s10534-006-9047-6.CrossRefPubMed
15.
Muhlenhoff U, Richhardt N, Gerber J, Lill R: Characterization of iron-sulfur protein assembly in isolated mitochondria. A requirement for ATP, NADH, and reduced iron. J Biol Chem. 2002, 277 (33): 29810-29816. 10.1074/jbc.M204675200.CrossRefPubMed
16.
Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, Cortopassi G: 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. 1999, 8 (3): 425-430. 10.1093/hmg/8.3.425.CrossRefPubMed
17.
Limenta LM, Jirasomprasert T, Tankanitlert J, Svasti S, Wilairat P, Chantharaksri U, Fucharoen S, Morales NP: UGT1A6 genotype-related pharmacokinetics of deferiprone (L1) in healthy volunteers. Br J Clin Pharmacol. 2008
18.
Young P, Leeds JM, Slabaugh MB, Mathews CK: Ribonucleotide reductase: evidence for specific association with HeLa cell mitochondria. Biochem Biophys Res Commun. 1994, 203 (1): 46-52. 10.1006/bbrc.1994.2146.CrossRefPubMed
Metadata
Title
Deferiprone targets aconitase: Implication for Friedreich's ataxia treatment
Authors
Sergio Goncalves
Vincent Paupe
Emmanuel P Dassa
Pierre Rustin
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2008
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/1471-2377-8-20

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