title: Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy.
abstract: Optic Atrophy 1 (OPA1) gene mutations cause diseases ranging from isolated dominant optic atrophy (DOA) to various multisystemic disorders. OPA1, a large GTPase belonging to the dynamin family, is involved in mitochondrial network dynamics. The majority of OPA1 mutations encodes truncated forms of the protein and causes DOA through haploinsufficiency, whereas missense OPA1 mutations are predicted to cause disease through deleterious dominant-negative mechanisms. We used 3D imaging and biochemical analysis to explore autophagy and mitophagy in fibroblasts from seven patients harbouring OPA1 mutations. We report new genotype-phenotype correlations between various types of OPA1 mutation and mitophagy. Fibroblasts bearing dominant-negative OPA1 mutations showed increased autophagy and mitophagy in response to uncoupled oxidative phosphorylation. In contrast, OPA1 haploinsufficiency was correlated with a substantial reduction in mitochondrial turnover and autophagy, unless subjected to experimental mitochondrial injury. Our results indicate distinct alterations of mitochondrial physiology and turnover in cells with OPA1 mutations, suggesting that the level and profile of OPA1 may regulate the rate of mitophagy.
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.
authors.forename: Mariame Selma
authors.initials: MS
authors.lastname: Kane
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Alban
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret-Dumas
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
authors.forename: Naïg
authors.initials: N
authors.lastname: Gueguen
authors.affiliation: RGM4645 Université Blaise Pascal, Aubière, France.
authors.forename: Layal
authors.initials: L
authors.lastname: Ishak
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferre
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6015, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.
authors.forename: Arnaud
authors.identifier: 0000-0002-5135-6643
authors.initials: A
authors.lastname: Chevrollier
mesh_terms: D000293:Adolescent; D000328:Adult; D001343:Autophagy / Q000235:genetics*; D002478:Cells, Cultured; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D063306:Mitophagy / Q000235:genetics; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human
keywords: OPA1; mitochondria; mitophagy; optic atrophy