title: Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models.
abstract: Increased levels of the mitochondria-shaping protein Opa1 improve respiratory chain efficiency and protect from tissue damage, suggesting that it could be an attractive target to counteract mitochondrial dysfunction. Here we show that Opa1 overexpression ameliorates two mouse models of defective mitochondrial bioenergetics. The offspring from crosses of a constitutive knockout for the structural complex I component Ndufs4 (Ndufs4(-/-)), and of a muscle-specific conditional knockout for the complex IV assembly factor Cox15 (Cox15(sm/sm)), with Opa1 transgenic (Opa1(tg)) mice showed improved motor skills and respiratory chain activities compared to the naive, non-Opa1-overexpressing, models. While the amelioration was modest in Ndufs4(-/-)::Opa1(tg) mice, correction of cristae ultrastructure and mitochondrial respiration, improvement of motor performance and prolongation of lifespan were remarkable in Cox15(sm/sm)::Opa1(tg) mice. Mechanistically, respiratory chain supercomplexes were increased in Cox15(sm/sm)::Opa1(tg) mice, and residual monomeric complex IV was stabilized. In conclusion, cristae shape amelioration by controlled Opa1 overexpression improves two mouse models of mitochondrial disease.
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," Milan, Italy; MRC-Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Civiletto
authors.affiliation: Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Varanita
authors.affiliation: MRC-Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Cerutti
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," Milan, Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gorletta
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Barbaro
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchet
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," Milan, Italy; MRC-Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.affiliation: Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy; Department of Biology, University of Padova, Padova, Italy. Electronic address: luca.scorrano@unipd.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
authors.affiliation: Fondazione IRCCS Istituto Neurologico "C. Besta," Milan, Italy; MRC-Mitochondrial Biology Unit, Cambridge, UK. Electronic address: mdz21@mrc-mbu.cam.ac.uk.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000818:Animals; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010101:Oxygen Consumption
chemical_list: C534449:Ndufs4 protein, mouse; D003576:Electron Transport Complex IV; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse; D042967:Electron Transport Complex I