Human Molecular Genetics Advance Access published online on March 11, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh108
© 2004 by Oxford University Press
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1 Department of Genetics Anthropology Evolution, University of Parma, 43100 Parma, Italy
* To whom correspondence should be addressed. E-mail: iferrero{at}unipr.it.
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) marked growth defect on non-fermentable carbon sources, and (b) 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 to wild-type AAC2. In order to study whether a dominant phenotype, like 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.
Article
Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations, lead to defective oxidative phosphorylation in Saccharomyces cerevisiae and affect mitochondrial DNA stability
2 Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70125 Bari, Italy; CNR Institute of Biomembranes and Bioenergetics, 70125 Bari, Italy
3 Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70125 Bari, Italy
4 Division of Molecular Neurogenetics, National Neurological Institute "C. Besta", 20126 Milano, Italy
5 Department of Genetics Anthropology Evolution, University of Parma, Parco Area delle Scienze 11/A, 43100 Parma, Italy
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