Friedreich's ataxia is a
hereditary neurodegenerative disease caused by reduced expression of mitochondrial
frataxin.
Frataxin deficiency causes impairment in respiratory capacity, disruption of
iron homoeostasis and
hypersensitivity to
oxidants. Although the redox properties of
NAD (NAD+ and
NADH) are essential for energy metabolism, only few results are available concerning homoeostasis of these
nucleotides in
frataxin-deficient cells. In the present study, we show that the
malate-
aspartate NADH shuttle is impaired in Saccharomyces cerevisiae
frataxin-deficient cells (Δyfh1) due to decreased activity of cytosolic and mitochondrial
isoforms of
malate dehydrogenase and to complete inactivation of the
mitochondrial aspartate aminotransferase (Aat1). A considerable decrease in the amount of mitochondrial acetylated
proteins was observed in the Δyfh1 mutant compared with wild-type. Aat1 is acetylated in wild-type mitochondria and deacetylated in Δyfh1 mitochondria suggesting that inactivation could be due to this post-translational modification. Mutants deficient in
iron-
sulfur cluster assembly or lacking
mitochondrial DNA also showed decreased activity of Aat1, suggesting that Aat1 inactivation was a secondary phenotype in Δyfh1 cells. Interestingly, deletion of the AAT1 gene in a wild-type strain caused respiratory deficiency and disruption of
iron homoeostasis without any sensitivity to oxidative stress. Our results show that secondary inactivation of Aat1 contributes to the amplification of the respiratory defect observed in Δyfh1 cells. Further implication of
mitochondrial protein deacetylation in the physiology of
frataxin-deficient cells is anticipated.