{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:33:05Z","timestamp":1790839985104,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,18]],"date-time":"2020-07-18T00:00:00Z","timestamp":1595030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007393","name":"Association Fran\u00e7aise contre les Myopathies","doi-asserted-by":"publisher","award":["22382"],"award-info":[{"award-number":["22382"]}],"id":[{"id":"10.13039\/100007393","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The National Science Center of Poland","award":["NSCP 2016\/23\/B\/NZ3\/02098"],"award-info":[{"award-number":["NSCP 2016\/23\/B\/NZ3\/02098"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Probing the pathogenicity and functional consequences of mitochondrial DNA (mtDNA) mutations from patient\u2019s 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&gt;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&gt;C mutation disrupts a four \u03b1-helix bundle in subunit a and that the leucine residue it targets indirectly optimizes proton conduction through the membrane domain of ATP synthase.<\/jats:p>","DOI":"10.3390\/ijms21145083","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T06:08:17Z","timestamp":1595225297000},"page":"5083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T&gt;C Mutation in Mitochondrial ATP6 Gene"],"prefix":"10.3390","volume":"21","author":[{"given":"Xin","family":"Su","sequence":"first","affiliation":[{"name":"Institut de Biochimie et G\u00e9n\u00e9tique Cellulaires, Universit\u00e9 de Bordeaux, 1 Rue Camille Saint-Sa\u00ebns, 33077 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7145-278X","authenticated-orcid":false,"given":"Alain","family":"Dautant","sequence":"additional","affiliation":[{"name":"Institut de Biochimie et G\u00e9n\u00e9tique Cellulaires, Universit\u00e9 de Bordeaux, 1 Rue Camille Saint-Sa\u00ebns, 33077 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Godard","sequence":"additional","affiliation":[{"name":"Institut de Biochimie et G\u00e9n\u00e9tique Cellulaires, Universit\u00e9 de Bordeaux, 1 Rue Camille Saint-Sa\u00ebns, 33077 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Bouhier","sequence":"additional","affiliation":[{"name":"Institut de Biochimie et G\u00e9n\u00e9tique Cellulaires, Universit\u00e9 de Bordeaux, 1 Rue Camille Saint-Sa\u00ebns, 33077 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9881-0516","authenticated-orcid":false,"given":"Teresa","family":"Zoladek","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8712-7535","authenticated-orcid":false,"given":"Roza","family":"Kucharczyk","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Paul","family":"di Rago","sequence":"additional","affiliation":[{"name":"Institut de Biochimie et G\u00e9n\u00e9tique Cellulaires, Universit\u00e9 de Bordeaux, 1 Rue Camille Saint-Sa\u00ebns, 33077 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2290-5375","authenticated-orcid":false,"given":"D\u00e9borah","family":"Tribouillard-Tanvier","sequence":"additional","affiliation":[{"name":"Institut de Biochimie et G\u00e9n\u00e9tique Cellulaires, Universit\u00e9 de Bordeaux, 1 Rue Camille Saint-Sa\u00ebns, 33077 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1126\/science.283.5407.1488","article-title":"Oxidative phosphorylation at the fin de siecle","volume":"283","author":"Saraste","year":"1999","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1146\/annurev.biochem.66.1.717","article-title":"The ATP synthase\u2014A splendid molecular machine","volume":"66","author":"Boyer","year":"1997","journal-title":"Annu. 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