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 Sco2KO/KI mouse. These results open new perspectives for therapy of mitochondrial disease. © 2011 Elsevier Inc.

Viscomi, C., Bottani, E., Civiletto, G., Cerutti, R., Moggio, M., Fagiolari, G., et al. (2011). In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis. CELL METABOLISM, 14(1), 80-90 [10.1016/j.cmet.2011.04.011].

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

BOTTANI, EMANUELA
Primo
;
CIVILETTO, GABRIELE;
2011

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 Sco2KO/KI mouse. These results open new perspectives for therapy of mitochondrial disease. © 2011 Elsevier Inc.
Articolo in rivista - Articolo scientifico
AMP-Activated Protein Kinases; Aminoimidazole Carboxamide; 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; Ribonucleotides; Signal Transduction; Trans-Activators; Transcription Factors; Cell Biology; Molecular Biology; Physiology
English
2011
14
1
80
90
none
Viscomi, C., Bottani, E., Civiletto, G., Cerutti, R., Moggio, M., Fagiolari, G., et al. (2011). In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis. CELL METABOLISM, 14(1), 80-90 [10.1016/j.cmet.2011.04.011].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/89242
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