Increased levels of plasma malondialdehyde in Friedreich ataxia.

Abstract

Friedreich ataxia is an autosomal recessive disease characterized by spinocerebellar degeneration and cardiomyopathy. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria.1 Most patients (95%) are homozygous for the hyperexpansion of a GAA repeat sequence in the first intron of the frataxin gene, which inhibits transcription; a few are heterozygous for a GAA expansion and a frataxin point mutation.1 Data from yeast suggest that frataxin deficiency results in mitochondrial dysfunction and free radical damage. Yeast cells with a disrupted frataxin homolog gene ( YFH1 ) show a 10-fold accumulation of iron in mitochondria, lose mitochondrial DNA, and become unable to carry out oxidative phosphorylation.2 Iron in mitochondria can amplify the toxicity of reactive oxygen species (ROS) leaking from the respiratory chain by producing the free hydroxyl radical (OH•) through Fenton chemistry [Fe(II) + H2O2 → Fe(III) + OH• + OH−]. Occurrence of the Fenton reaction in ΔYFH1 yeast cells is suggested by their enhanced sensitivity to H2O2.2 Several lines of evidence support the hypothesis that similar mechanisms are involved in the human disease. First, patients with Friedreich ataxia have iron deposits in the heart …