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Aconitase and mitochondrial iron–sulphur protein deficiency in Friedreich ataxia

Abstract

Friedreich ataxia (FRDA) is a common autosomal recessive degenerative disease (1/50,000 live births) characterized by a progressive gait and limb ataxia with lack of tendon reflexes in the legs, dysarthria and pyramidal weakness of the inferior limbs1,2. Hypertrophic cardiomyopathy is observed in most FRDA patients. The gene associated with the disease has been mapped to chromosome 9q13 (ref. 3) and encodes a 210-amino-acid protein, frataxin. FRDA is caused primarily by a GAA repeat expansion within the first intron of the frataxin gene, which accounts for 98% of mutant alleles4. The function of the protein is unknown, but an increased iron content has been reported in hearts of FRDA patients5 and in mitochondria of yeast strains carrying a deleted frataxin gene counterpart (YFH1), suggesting that frataxin plays a major role in regulating mitochondria! iron transport6,7. Here, we report a deficient activity of the iron-sulphur (Fe-S) cluster-containing subunits of mitochondrial respiratory complexes I, II and III in the endomyocardial biopsy of two unrelated FRDA patients. Aconitase, an iron-sulphur protein involved in iron homeostasis, was found to be deficient as well. Moreover, disruption of the YFH1 gene resulted in multiple Fe-S–dependent enzyme deficiencies in yeast. The deficiency of Fe-S–dependent enzyme activities in both FRDA patients and yeast should be related to mitochondrial iron accumulation, especially as Fe-S proteins are remarkably sensitive to free radicals8. Mutated frataxin triggers aconitase and mitochondrial Fe-S respiratory enzyme deficiency in FRDA, which should therefore be regarded as a mitochondrial disorder.

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References

  1. Geoffroy, G. et al. Clinical description and roentgenologic evaluation of patients with Friedreich's ataxia. Can. J. Neurol. Sci. 3, 279–286 (1976).

    Article  CAS  PubMed  Google Scholar 

  2. Harding, A.E. Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 104, 598–620 (1981).

    Article  Google Scholar 

  3. Chamberlain, S. et al. Genetic homogeneity of the Friedreich ataxia locus on chromosome 9. Am. J. Hum. Genet. 44, 518–521 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Campuzano, V. et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Sanchez-Casis, G., Cote, M. & Barbeau, A. Pathology of the heart in FriedreichS ataxia: review of the literature and report of one case. Can. J. Neurol. Sci. 3, 349–354 (1977).

    Article  Google Scholar 

  6. Babcock, M. et al. Regulation of mitochondrial iron accumulation by Yfhlp, a putative homolog of frataxin. Science 276, 1709–1712 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Foury, F. & Cazzalini, O. Deletion of the yeast homologue of the human gene associated with Friedreich's ataxia elicits iron accumulation in mitochondria. FEBS Lett. 411, 373–377 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Fridovitch, I. Superoxide radical and superoxide dismutases. Annu. Rev. Biochem. 64, 97–112 (1995).

    Article  Google Scholar 

  9. Cedarbaum, J.M. & Blass, J.P. Mitochondrial dysfunction and spinocerebellar degenerations. Neurochem. Pathol. 4, 43–63 (1986).

    Article  CAS  PubMed  Google Scholar 

  10. Koutnitkova, H. et al. Studies of human, mouse and yeast homologues indicate a mitochondrial function for the frataxin. Nature Genet. 16, 345–351 (1997).

    Article  Google Scholar 

  11. Rustin, P. et al. Endomyocardial biopsy for early detection of mitochondrial disorders in hypertrophiccardiomyopathies. J. Pediatr. 124, 224–228 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Rustin, P. et al. Assessment of the mitochondrial respiratory chain (letter). Lancet 338, 60 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Jacq, C. et al. The nucleotide sequence of Saccharomyces cerevisiae chromosome IV. Nature 387 (Suppl) 75–78 (1997).

    CAS  PubMed  Google Scholar 

  14. Kaptain, S. et al. A regulated RNA binding protein also possesses aconitase activity. Proc. Natl. Acad Sci. USA 88, 10109–10113 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hentze, M.W. & Kühn, L.C. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl. Acad. Sci. USA 93, 8175–8182 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li, Y. et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nature Genet. 11, 376–381 (1996).

    Article  Google Scholar 

  17. Filla, A. et al. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am. J. Hum. Genet. 59, 554–560 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Paul, R., Santucci, S., Saunières, A., Desnuelle, C. & Paquis-Flucklinger, V. Rapid mapping of mitochondrial DNA deletions by large fragment PCR. Trends Genet. 12, 131–132 (1996).

    CAS  PubMed  Google Scholar 

  19. Rickwood, D., Wilson, M.T. & Darley-Usmar, V.M. Isolation and characteristics of intact mitochondria, in Mitochondria: A Practical Approach (eds Darley-Usmar, V. M., Rickwood, D. & Wilson, M.T.) 1–16 (IRL, Oxford, UK, (1987).

    Google Scholar 

  20. Rustin, P. et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin. Chim. Acta 228, 35–51 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Robinson, J.B., Brent, L.G., Sumegi, B. & Srere, P.A. An enzymatic approach to the study of the Krebs tricarboxylic acid cycle, in Mitochondria: A Practical Approach (eds Darley-Usmar, V. M., Rickwood, D. & Wilson, M.T.) 153–170 (IRL, Oxford, UK, (1987).

    Google Scholar 

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Correspondence to Arnold Munnich.

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Rötig, A., de Lonlay, P., Chretien, D. et al. Aconitase and mitochondrial iron–sulphur protein deficiency in Friedreich ataxia. Nat Genet 17, 215–217 (1997). https://doi.org/10.1038/ng1097-215

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