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Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene

Probing the pathogenicity and functional consequences of mitochondrial DNA (mtDNA) mutations from patient’s cells and tissues is difficult due to genetic heteroplasmy (co-existence of wild type and mutated mtDNA in cells), occurrence of numerous mtDNA polymorphisms, and absence of methods for geneti...

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Autores principales: Su, Xin, Dautant, Alain, Godard, François, Bouhier, Marine, Zoladek, Teresa, Kucharczyk, Roza, di Rago, Jean-Paul, Tribouillard-Tanvier, Déborah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404254/
https://www.ncbi.nlm.nih.gov/pubmed/32708436
http://dx.doi.org/10.3390/ijms21145083
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author Su, Xin
Dautant, Alain
Godard, François
Bouhier, Marine
Zoladek, Teresa
Kucharczyk, Roza
di Rago, Jean-Paul
Tribouillard-Tanvier, Déborah
author_facet Su, Xin
Dautant, Alain
Godard, François
Bouhier, Marine
Zoladek, Teresa
Kucharczyk, Roza
di Rago, Jean-Paul
Tribouillard-Tanvier, Déborah
author_sort Su, Xin
collection PubMed
description Probing the pathogenicity and functional consequences of mitochondrial DNA (mtDNA) mutations from patient’s cells and tissues is difficult due to genetic heteroplasmy (co-existence of wild type and mutated mtDNA in cells), occurrence of numerous mtDNA polymorphisms, and absence of methods for genetically transforming human mitochondria. Owing to its good fermenting capacity that enables survival to loss-of-function mtDNA mutations, its amenability to mitochondrial genome manipulation, and lack of heteroplasmy, Saccharomyces cerevisiae is an excellent model for studying and resolving the molecular bases of human diseases linked to mtDNA in a controlled genetic background. Using this model, we previously showed that a pathogenic mutation in mitochondrial ATP6 gene (m.9191T>C), that converts a highly conserved leucine residue into proline in human ATP synthase subunit a (aL222P), severely compromises the assembly of yeast ATP synthase and reduces by 90% the rate of mitochondrial ATP synthesis. Herein, we report the isolation of intragenic suppressors of this mutation. In light of recently described high resolution structures of ATP synthase, the results indicate that the m.9191T>C mutation disrupts a four α-helix bundle in subunit a and that the leucine residue it targets indirectly optimizes proton conduction through the membrane domain of ATP synthase.
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spelling pubmed-74042542020-08-11 Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene Su, Xin Dautant, Alain Godard, François Bouhier, Marine Zoladek, Teresa Kucharczyk, Roza di Rago, Jean-Paul Tribouillard-Tanvier, Déborah Int J Mol Sci Article Probing the pathogenicity and functional consequences of mitochondrial DNA (mtDNA) mutations from patient’s cells and tissues is difficult due to genetic heteroplasmy (co-existence of wild type and mutated mtDNA in cells), occurrence of numerous mtDNA polymorphisms, and absence of methods for genetically transforming human mitochondria. Owing to its good fermenting capacity that enables survival to loss-of-function mtDNA mutations, its amenability to mitochondrial genome manipulation, and lack of heteroplasmy, Saccharomyces cerevisiae is an excellent model for studying and resolving the molecular bases of human diseases linked to mtDNA in a controlled genetic background. Using this model, we previously showed that a pathogenic mutation in mitochondrial ATP6 gene (m.9191T>C), that converts a highly conserved leucine residue into proline in human ATP synthase subunit a (aL222P), severely compromises the assembly of yeast ATP synthase and reduces by 90% the rate of mitochondrial ATP synthesis. Herein, we report the isolation of intragenic suppressors of this mutation. In light of recently described high resolution structures of ATP synthase, the results indicate that the m.9191T>C mutation disrupts a four α-helix bundle in subunit a and that the leucine residue it targets indirectly optimizes proton conduction through the membrane domain of ATP synthase. MDPI 2020-07-18 /pmc/articles/PMC7404254/ /pubmed/32708436 http://dx.doi.org/10.3390/ijms21145083 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Su, Xin
Dautant, Alain
Godard, François
Bouhier, Marine
Zoladek, Teresa
Kucharczyk, Roza
di Rago, Jean-Paul
Tribouillard-Tanvier, Déborah
Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene
title Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene
title_full Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene
title_fullStr Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene
title_full_unstemmed Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene
title_short Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene
title_sort molecular basis of the pathogenic mechanism induced by the m.9191t>c mutation in mitochondrial atp6 gene
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404254/
https://www.ncbi.nlm.nih.gov/pubmed/32708436
http://dx.doi.org/10.3390/ijms21145083
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