Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans.

TitleGenetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans.
Publication TypeJournal Article
Year of Publication2006
AuthorsBaruffini, E, Lodi, T, Dallabona, C, Puglisi, A, Zeviani, M, Ferrero, I
JournalHum Mol Genet
Volume15
Issue19
Pagination2846-55
Date Published2006 Oct 01
ISSN0964-6906
KeywordsBase Sequence, Deoxyribonucleotides, DNA Polymerase gamma, DNA Polymerase I, DNA, Fungal, DNA, Mitochondrial, DNA-Directed DNA Polymerase, Humans, Mitochondria, Mutation, Ophthalmoplegia, Chronic Progressive External, Phenotype, Reactive Oxygen Species, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Trefoil Factor-2
Abstract

The human POLG gene encodes the catalytic subunit of mitochondrial DNA polymerase gamma (pol gamma). Mutations in pol gamma 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 gamma mutations. To shed light on the pathogenic mechanisms leading to these phenotypes, we have 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 (rho-) or no (rho0) mtDNA. Mutations in genes that control the mitochondrial supply of deoxynucleotides (dNTP) affect the mtDNA integrity in both humans and yeast. To test whether the manipulation of the dNTP pool can modify the effects of pol gamma mutations in yeast, we have 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 gamma mutations in yeast and, possibly, in humans.

DOI10.1093/hmg/ddl219
Alternate JournalHum. Mol. Genet.
Citation Key10.1093/hmg/ddl219
PubMed ID16940310
Grant ListGGP030039 / / Telethon / Italy