Opa1 Overexpression Ameliorates the Phenotype of Two Mitochondrial Disease Mouse Models

• Published in: Cell metabolism 2015-06, Vol.21 (6), p.845-854
• Main Authors: Civiletto, Gabriele, Varanita, Tatiana, Cerutti, Raffaele, Gorletta, Tatiana, Barbaro, Serena, Marchet, Silvia, Lamperti, Costanza, Viscomi, Carlo, Scorrano, Luca, Zeviani, Massimo
• Format: Article
• Language: English
• Subjects: Animals; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Electron Transport Complex IV - genetics; Electron Transport Complex IV - metabolism; Gene Expression Regulation, Enzymologic; GTP Phosphohydrolases - biosynthesis; GTP Phosphohydrolases - genetics; Mice; Mice, Knockout; Mitochondria - enzymology; Mitochondria - genetics; Mitochondria - pathology; Mitochondrial Diseases - enzymology; Mitochondrial Diseases - genetics; Mitochondrial Diseases - pathology; Oxygen Consumption
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2015.04.016

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 (Cox15sm/sm), with Opa1 transgenic (Opa1tg) mice showed improved motor skills and respiratory chain activities compared to the naive, non-Opa1-overexpressing, models. While the amelioration was modest in Ndufs4−/−::Opa1tg mice, correction of cristae ultrastructure and mitochondrial respiration, improvement of motor performance and prolongation of lifespan were remarkable in Cox15sm/sm::Opa1tg mice. Mechanistically, respiratory chain supercomplexes were increased in Cox15sm/sm::Opa1tg mice, and residual monomeric complex IV was stabilized. In conclusion, cristae shape amelioration by controlled Opa1 overexpression improves two mouse models of mitochondrial disease. [Display omitted] •Opa1 overexpression improves the phenotype of Ndufs4−/− and Cox15sm/sm mice•O2 consumption rate and respiratory chain activities are increased in double mutants•Mitochondrial ultrastructure is corrected by Opa1 overexpression in Cox15sm/sm•Respiratory complexes and supercomplexes are stabilized in Cox15sm/sm::Opa1tg Although mitochondrial diseases have diverse causes, they are all characterized by defective oxidative phosphorylation. Civiletto et al. show that overexpression of the mitochondria-shaping protein OPA1, which improves respiratory chain efficiency, improves the phenotypes of two pre-clinical models of defective mitochondrial bioenergetics.