Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia

Nat Genet. 1997 Oct;17(2):215-7. doi: 10.1038/ng1097-215.


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 limbs. 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 alleles. The function of the protein is unknown, but an increased iron content has been reported in hearts of FRDA patients and in mitochondria of yeast strains carrying a deleted frataxin gene counterpart (YFH1), suggesting that frataxin plays a major role in regulating mitochondrial iron transport. 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 radicals. Mutated frataxin triggers aconitase and mitochondrial Fe-S respiratory enzyme deficiency in FRDA, which should therefore be regarded as a mitochondrial disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitate Hydratase / deficiency*
  • Citric Acid Cycle
  • Electron Transport
  • Endocardium / metabolism
  • Frataxin
  • Friedreich Ataxia / genetics
  • Friedreich Ataxia / metabolism*
  • Genes, Fungal
  • Humans
  • Iron / metabolism
  • Iron-Binding Proteins*
  • Iron-Sulfur Proteins / deficiency*
  • Mitochondria / metabolism*
  • Models, Biological
  • Mutation
  • Myocardium / metabolism
  • Oxidative Stress
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism


  • Iron-Binding Proteins
  • Iron-Sulfur Proteins
  • Iron
  • Phosphotransferases (Alcohol Group Acceptor)
  • Aconitate Hydratase