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

Abstract

SummaryIncreased 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.

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

“…Studies with bezofibrate suggest that it is of moderate use in humans suffering from mutations in carnitine palmitoyltransferase II deficiency (Bonnefont et al 2009). Data on bezofibrate's ability to correct the phenotypes associated with mutations in respiratory complex proteins, in contrast, have been confined largely to mouse models and have yielded very mixed results (Wenz et al 2008;Viscomi et al 2011;Yatsuga and Suomalainen 2012). The major limitation of fibrates is that they target only a single cognate transcription factor of PGC-1a, namely, PPARa, which is involved in up-regulation of the mitochondrial proteome.…”

“…High throughput screenings for compounds that improve the growth and ATP levels of fibroblasts from humans with a complex I deficiency revealed the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) as one of the most efficacious molecules (Golubitzky et al 2011). In several mouse models of cytochrome c oxidase deficiency, AICAR treatment was also shown to lead to a partial rescue of COXIV activity and some measure of improvement in motor performance (Viscomi et al 2011).…”

“…As mentioned earlier, transgenic overexpression of PGC-1a has been shown to significantly blunt the pathological effects of cytochrome c oxidase (Viscomi et al 2011), COXIV deficiency in mice (Lin et al 2002;Wenz et al 2008), and COXIII/ IV deficiency in human patient-derived cell lines. Thus, small molecule therapies that potentiate PGC-1a function or the function of one of its cognate transcription factors could yield tangible benefits.…”

“…In skeletal muscle, the increased mitochondrial biogenesis caused by transgenic overexpression of PGC-1a can attenuate the development of mitochondrial disease in mouse models of respiratory complex IV/cytochrome c oxidase deficiencies (Lin et al 2002;Wenz et al 2008;Viscomi et al 2011). It has also been shown that PGC-1a/b expression improves mitochondrial respiration capacity in cells from human patients with a complex III or IV deficiency (Srivastava et al 2009).…”

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

“…[32,95,96]). The latter might explain the positive effects of AICAR in animal models of mitochondrial disease and fibroblast from patients with mitochondrial dysfunction [97,98].…”