In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis.

TitleIn vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis.
Publication TypeJournal Article
Year of Publication2011
AuthorsViscomi, C, Bottani, E, Civiletto, G, Cerutti, R, Moggio, M, Fagiolari, G, Schon, EA, Lamperti, C, Zeviani, M
JournalCell Metab
Date Published2011 Jul 06
KeywordsAminoimidazole Carboxamide, AMP-Activated Protein Kinases, Animals, Bezafibrate, Cytochrome-c Oxidase Deficiency, Disease Models, Animal, Electron Transport Complex IV, Gene Knock-In Techniques, Hypoglycemic Agents, Hypolipidemic Agents, Membrane Proteins, Mice, Mice, Knockout, Mice, Transgenic, Mitochondrial Proteins, Muscle, Skeletal, Oxidative Phosphorylation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Ribonucleotides, Signal Transduction, Trans-Activators, Transcription Factors

Increased mitochondrial biogenesis by activation of PPAR- or AMPK/PGC-1α-dependent homeostatic pathways has been proposed as a treatment for mitochondrial disease. We tested this hypothesis on three recombinant mouse models characterized by defective cytochrome c-oxidase (COX) activity: a knockout (KO) mouse for Surf1, a knockout/knockin mouse for Sco2, and a muscle-restricted KO mouse for Cox15. First, we demonstrated that double-recombinant animals overexpressing PGC-1α in skeletal muscle on a Surf1 KO background showed robust induction of mitochondrial biogenesis and increase of mitochondrial respiratory chain activities, including COX. No such effect was obtained by treating both Surf1(-/-) and Cox15(-/-) mice with the pan-PPAR agonist bezafibrate, which instead showed adverse effects in either model. Contrariwise, treatment with the AMPK agonist AICAR led to partial correction of COX deficiency in all three models, and, importantly, significant motor improvement up to normal in the Sco2(KO/KI) mouse. These results open new perspectives for therapy of mitochondrial disease.

Alternate JournalCell Metab.
Citation Key10.1016/j.cmet.2011.04.011
PubMed ID21723506
PubMed Central IDPMC3130927
Grant ListGGP07019 / / Telethon / Italy
HD32062 / HD / NICHD NIH HHS / United States
GTF07004 / / Telethon / Italy
P01 HD032062 / HD / NICHD NIH HHS / United States
GPP10005 / / Telethon / Italy