Defining the impact on yeast ATP synthase of two pathogenic human mitochondrial DNA mutations, T9185C and T9191C

Biochimie. 2014 May:100:200-6. doi: 10.1016/j.biochi.2013.11.024. Epub 2013 Dec 4.


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.

Keywords: ATP synthase; ATP6; Disease; Energetics; Mitochondria; mtDNA mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis*
  • Charcot-Marie-Tooth Disease / enzymology
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / pathology
  • Gene Expression
  • Genotype
  • Humans
  • Leigh Disease / enzymology
  • Leigh Disease / genetics
  • Leigh Disease / pathology
  • Mitochondria / enzymology
  • Mitochondria / genetics*
  • Mitochondrial Proton-Translocating ATPases / chemistry
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Models, Biological
  • Mutation*
  • Oxidative Phosphorylation
  • Phenotype
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Severity of Illness Index


  • ATP6 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Adenosine Triphosphate
  • Mitochondrial Proton-Translocating ATPases