ACONITASE AND MITOCHONDRIAL IRON-SULFUR PROTEIN-DEFICIENCY IN FRIEDREICH ATAXIA

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(1,2). Hypertrophic cardiomyop athy is observed in most FRDA patients. The gene associated with the d isease has been mapped to chromosome 9q13 (ref. 3) and encodes a 210-a mino-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(4). The function of the protein is unknown, but an increased iron content has been reported in hearts of FRDA pat ients(5) and the mitochondria of yeast strains carrying a deleted frat axin gene counterpart (YFH1), suggesting that frataxin plays a major r ole in regulating mitochondrial iron transport(6.7). Here, we report a deficient activity of the iron-sulphur (Fe-S) cluster-containing subu nits of mitochondrial respiratory complexes I, II and III in the endom yocardial biopsy of two unrelated FRDA patients. Aconitase, an iron-su lphur 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-depe ndent enzyme activities in both FRDA patients and yeast should be rela ted to mitochondrial iron accumulation, especially as Fe-S proteins ar e remarkably sensitive to free radicals(8). Mutated frataxin triggers aconitase and mitochondrial Fe-S respiratory enzyme deficiency in FRDA , which should therefore be regarded as a mitochondrial disorder.