In Vivo Correction of COX Deficiency by Activation of the AMPK/PGC-1α Axis

TLDR

Mitochondrial biogenesis via PPAR or AMPK/PGC‑1α pathways has been proposed as a therapy for mitochondrial disease. The study tested whether activating these pathways could correct COX deficiency in three mouse models (Surf1 KO, Sco2 KO/KI, Cox15 KO). The authors overexpressed PGC‑1α in skeletal muscle of Surf1 KO mice and treated Surf1, Cox15, and Sco2 models with the pan‑PPAR agonist bezafibrate or the AMPK agonist AICAR to assess mitochondrial biogenesis and COX activity. PGC‑1α overexpression induced mitochondrial biogenesis and restored COX activity in Surf1 KO mice, bezafibrate had no effect and caused adverse outcomes, while AICAR partially corrected COX deficiency in all models and markedly improved motor function in the Sco2 KO/KI mouse, indicating therapeutic promise.

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.