title: A yeast model of the neurogenic ataxia retinitis pigmentosa (NARP) T8993G mutation in the mitochondrial ATP synthase-6 gene.
abstract: NARP (neuropathy, ataxia, and retinitis pigmentosa) and MILS (maternally inherited Leigh syndrome) are mitochondrial disorders associated with point mutations of the mitochondrial DNA (mtDNA) in the gene encoding the Atp6p subunit of the ATP synthase. The most common and studied of these mutations is T8993G converting the highly conserved leucine 156 into arginine. We have introduced this mutation at the corresponding position (183) of yeast Saccharomyces cerevisiae mitochondrially encoded Atp6p. The "yeast NARP mutant" grew very slowly on respiratory substrates, possibly because mitochondrial ATP synthesis was only 10% of the wild type level. The mutated ATP synthase was found to be correctly assembled and present at nearly normal levels (80% of the wild type). Contrary to what has been reported for human NARP cells, the reverse functioning of the ATP synthase, i.e. ATP hydrolysis in the F(1) coupled to F(0)-mediated proton translocation out of the mitochondrial matrix, was significantly compromised in the yeast NARP mutant. Interestingly, the oxygen consumption rate in the yeast NARP mutant was decreased by about 80% compared with the wild type, due to a selective lowering in cytochrome c oxidase (complex IV) content. This finding suggests a possible regulatory mechanism between ATP synthase activity and complex IV expression in yeast mitochondria. The availability of a yeast NARP model could ease the search for rescuing mechanisms against this mitochondrial disease.
authors.affiliation: Institut de Biochimie et Génétique Cellulaires CNRS, Université Victor Segalen Bordeaux 2, 1 Rue Camille Saint-Saëns, Bordeaux Cedex, France.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Rak
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tetaud
authors.forename: Stéphane
authors.initials: S
authors.lastname: Duvezin-Caubet
authors.forename: Nahia
authors.initials: N
authors.lastname: Ezkurdia
authors.forename: Maïlis
authors.initials: M
authors.lastname: Bietenhader
authors.forename: Joanna
authors.initials: J
authors.lastname: Rytka
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: di Rago
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000235:genetics; D019943:Amino Acid Substitution; D001259:Ataxia / Q000201:enzymology* / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D006868:Hydrolysis; D007888:Leigh Disease / Q000201:enzymology*; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D020125:Mutation, Missense; D010101:Oxygen Consumption / Q000235:genetics; D011522:Protons; D012174:Retinitis Pigmentosa / Q000201:enzymology* / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C501004:ATP6 protein, S cerevisiae; D011522:Protons; D029701:Saccharomyces cerevisiae Proteins; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D025261:Mitochondrial Proton-Translocating ATPases