Increased mitochondrial biogenesis by activation of PPAR- or AMPK/PGC-1 alpha-dependent homeostatic pathways has been proposed as a treatment for mitochondria! 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-1 alpha 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.

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

Bottani, E.;
2011

Abstract

Increased mitochondrial biogenesis by activation of PPAR- or AMPK/PGC-1 alpha-dependent homeostatic pathways has been proposed as a treatment for mitochondria! 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-1 alpha 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.
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
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ribonucleotides
Signal Transduction
Trans-Activators
Transcription Factors
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1030670
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