title: Defining the impact on yeast ATP synthase of two pathogenic human mitochondrial DNA mutations, T9185C and T9191C.
abstract: Mutations in the human mitochondrial ATP6 gene encoding ATP synthase subunit a/6 (referred to as Atp6p in yeast) are at the base of neurodegenerative disorders like Neurogenic Ataxia and Retinitis Pigmentosa (NARP), Leigh syndrome (LS), Charcot-Marie-Tooth (CMT), and ataxia telangiectasia. In previous studies, using the yeast Saccharomyces cerevisiae as a model we were able to better define how several of these mutations impact the ATP synthase. Here we report the construction of yeast models of two other ATP6 pathogenic mutations, T9185C and T9191C. The first one was reported as conferring a mild, sometimes reversible, CMT clinical phenotype; the second one has been described in a patient presenting with severe LS. We found that an equivalent of the T9185C mutation partially impaired the functioning of yeast ATP synthase, with only a 30% deficit in mitochondrial ATP production. An equivalent of the mutation T9191C had much more severe effects, with a nearly complete block in yeast Atp6p assembly and an >95% drop in the rate of ATP synthesis. These findings provide a molecular basis for the relative severities of the diseases induced by T9185C and T9191C.
authors: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland; Institut de Biochimie et Génétique Cellulaires, CNRS UMR5095, Université Bordeaux Segalen, 1 Rue Camille Saint-Saëns, Bordeaux 33077 cedex, France.
authors: Anna Magdalena
authors: AM
authors: Kabala
authors: Institut de Biochimie et Génétique Cellulaires, CNRS UMR5095, Université Bordeaux Segalen, 1 Rue Camille Saint-Saëns, Bordeaux 33077 cedex, France.
authors: Jean-Paul
authors: JP
authors: Lasserre
authors: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors: Sharon H
authors: SH
authors: Ackerman
authors: Institut de Biochimie et Génétique Cellulaires, CNRS UMR5095, Université Bordeaux Segalen, 1 Rue Camille Saint-Saëns, Bordeaux 33077 cedex, France.
authors: Jean-Paul
authors: JP
authors: di Rago
authors: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland. Electronic address: roza@ibb.waw.pl.
authors: Roza
authors: R
authors: Kucharczyk
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D002607:Charcot-Marie-Tooth Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007888:Leigh Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010085:Oxidative Phosphorylation; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: C501004:ATP6 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases
keywords: ATP synthase; ATP6; Disease; Energetics; Mitochondria; mtDNA mutation