Human Molecular Genetics Advance Access published online on August 29, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl219
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1 Department of Genetics, Biology of Microrganisms, Anthropology, Evolution, University of Parma, 43100 Parma, Italy; Institut des sciences de la vie, Faculté d'Ingénierie biologique, Université Catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium
* To whom correspondence should be addressed. The human POLG gene encodes the catalytic subunit of mitochondrial DNA polymerase
Received June 20, 2006
Accepted August 2, 2006
Article
Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans
Enrico Baruffini 1, Tiziana Lodi 2, Cristina Dallabona 2, Andrea Puglisi 3, Massimo Zeviani 4 *, and Iliana Ferrero 2
2 Department of Genetics, Biology of Microrganisms, Anthropology, Evolution, University of Parma, 43100 Parma, Italy
3 Department of Molecular Biology and NCCR Program "Frontiers in Genetics", University of Geneva, Sciences III, CH-1211, Geneva 4, Switzerland
4 Pierfranco and Luisa Mariani Center for Mitochondrial Disease, Division of Molecular Neurogenetics, National Neurological Institute "C. Besta", Via Temolo 4, 20126 Milano, Italy
Massimo Zeviani, E-mail: zeviani{at}istituto-besta.it
Abstract 
? pol . Mutations in pol are associated with a spectrum of disease phenotypes including autosomal dominant and recessive forms of progressive external ophthalmoplegia, spino-cerebellar ataxia and epilepsy, and Alpers-Huttenlocher hepatocerebral poliodystrophy. Multiple deletions, or depletion of mtDNA in affected tissues are the molecular hallmarks of pol mutations. To shed light on the pathogenic mechanisms leading to these phenotypes, we introduced in MIP1, the yeast homologue of POLG, two mutations equivalent to the human Y955C and G268A mutations, which are associated with dominant and recessive PEO respectively. Both mutations induced the generation of petite colonies, carrying either rearranged (
-) or no (°) mtDNA. Mutations in genes that control the mitochondrial supply of deoxynucleotides (dNTP) affect the mtDNA integrity in both humans and yeast. To test as whether the manipulation of the dNTP pool can modify the effects of pol mutations in yeast, we overexpressed a dNTP checkpoint enzyme, ribonucleotide reductase, RNR1, or deleted its inhibitor, SML1. In both mutant strains the petite mutability was dramatically reduced. The same result was obtained by exposing the mutant strains to dihydrolipoic acid, an anti-oxidant agent. Therefore, an increase of the mitochondrial dNTP pool and/or a decrease of reactive oxygen species can prevent the mtDNA damage induced by pol mutations in yeast and, possibly, in humans.
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