Defining the impact on yeast ATP synthase of two pathogenic human mitochondrial DNA mutations, T9185C and T9191C
Biochimie. 2014-05-01; 100: 200-206
DOI: 10.1016/j.biochi.2013.11.024
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1. Biochimie. 2014 May;100:200-6. doi: 10.1016/j.biochi.2013.11.024. Epub 2013 Dec
4.
Defining the impact on yeast ATP synthase of two pathogenic human mitochondrial
DNA mutations, T9185C and T9191C.
Kabala AM(1), Lasserre JP(2), Ackerman SH(3), di Rago JP(2), Kucharczyk R(4).
Author information:
(1)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.
(2)Institut de Biochimie et Génétique Cellulaires, CNRS UMR5095, Université
Bordeaux Segalen, 1 Rue Camille Saint-Saëns, Bordeaux 33077 cedex, France.
(3)Department of Biochemistry and Molecular Biology, Wayne State University
School of Medicine, Detroit, MI, USA.
(4)Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw,
Poland. Electronic address: .
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.
Copyright © 2013 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.biochi.2013.11.024
PMID: 24316278 [Indexed for MEDLINE]