title: In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis.
abstract: 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.
authors: Unit of Molecular Neurogenetics, The Foundation Carlo Besta Institute of Neurology-IRCCS, Milan, Italy.
authors: Carlo
authors: C
authors: Viscomi
authors: Emanuela
authors: E
authors: Bottani
authors: Gabriele
authors: G
authors: Civiletto
authors: Raffaele
authors: R
authors: Cerutti
authors: Maurizio
authors: M
authors: Moggio
authors: Gigliola
authors: G
authors: Fagiolari
authors: Eric A
authors: EA
authors: Schon
authors: Costanza
authors: C
authors: Lamperti
authors: Massimo
authors: M
authors: Zeviani
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D030401:Cytochrome-c Oxidase Deficiency / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones; D018482:Muscle, Skeletal / Q000378:metabolism; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012265:Ribonucleotides / Q000627:therapeutic use; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012265:Ribonucleotides; C511423:SCO2 protein, mouse; C092928:Surf-1 protein; D015534:Trans-Activators; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D003576:Electron Transport Complex IV; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D001629:Bezafibrate