Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models.

TitleOpa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models.
Publication TypeJournal Article
Year of Publication2015
AuthorsCiviletto, G, Varanita, T, Cerutti, R, Gorletta, T, Barbaro, S, Marchet, S, Lamperti, C, Viscomi, C, Scorrano, L, Zeviani, M
JournalCell Metab
Date Published2015 Jun 02
KeywordsAnimals, Electron Transport Complex I, Electron Transport Complex IV, Gene Expression Regulation, Enzymologic, GTP Phosphohydrolases, Mice, Mice, Knockout, Mitochondria, Mitochondrial Diseases, Oxygen Consumption

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.

Alternate JournalCell Metab.
Citation Key10.1016/j.cmet.2015.04.016
PubMed ID26039449
PubMed Central IDPMC4457891
Grant ListGGP11011 / / Telethon / Italy
MC_UP_1002/1 / / Medical Research Council / United Kingdom
322424 / / European Research Council / International
GGP12162 / / Telethon / Italy
GGP14187 / / Telethon / Italy
GPP10005 / / Telethon / Italy