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Autosomal dominant and recessive forms of progressive external ophthalmoplegia (adPEO and arPEO) are mitochondrial disorders characterized by the presence of multiple deletions of mitochondrial DNA in affected tissues. Four adPEO-associated missense mutations have been identified in the ANT1 gene. In order to investigate their functional consequences on cellular physiology, we introduced three of them at equivalent positions in  AAC2 , the yeast orthologue of human ANT1. We demonstrate here that expression of the equivalent mutations in  aac2 -defective haploid strains of  Saccharomyces cerevisiae  results in (a) a marked growth defect on non-fermentable carbon sources, and (b) a concurrent reduction of the amount of mitochondrial cytochromes, cytochrome c oxidase activity and cellular respiration. The efficiency of ATP and ADP transport was variably affected by the different  AAC2  mutations. However, irrespective of the absolute level of activity, the  AAC2  pathogenic mutants showed a significant defect in ADP versus ATP transport compared with wild-type  AAC2.  In order to study whether a dominant phenotype, as in humans, could be observed, the  aac2  mutant alleles were also inserted in combination with the endogenous wild-type  AAC2  gene. The heteroallelic strains behaved as recessive for oxidative growth and  petite -negative phenotype. In contrast, reduction in cytochrome content and increased mtDNA instability appeared to behave as dominant traits in heteroallelic strains. Our results indicate that  S. cerevisiae  is a suitable  in vivo  model to study the pathogenicity of the human ANT1 mutations and the pathophysiology leading to impairment of oxidative phosphorylation and damage of mtDNA integrity, as found in adPEO.

human molecular genetics

Mutations in  AAC2 , equivalent to human adPEO-associated ANT1 mutations, lead to defective oxidative phosphorylation in  Saccharomyces cerevisiae  and affect mitochondrial DNA stability