Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response.

There is increasing evidence that longevity and stress resistance are connected, but the mechanism is unclear. We report that mitochondria are regulated in response to oxidative stress and calorie restriction through a shared mechanism involving peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha). We demonstrate that PGC-1alpha subcellular distribution is regulated, and its transcriptional activity is promoted through SIRT1-dependent nuclear accumulation. In addition, the duration of PGC-1alpha activity is regulated by glycogen synthase kinase beta (GSK3beta), which targets PGC-1alpha for intranuclear proteasomal degradation. This mechanism of regulation permits the rapidity and persistence of PGC-1alpha activation to be independently controlled. We provide evidence that this pathway of PGC-1alpha regulation occurs in vivo in mice, both in the oxidative stress response and with calorie restriction. Our data show how mitochondrial function may be adapted in response to external stimuli, and support the concept that such adaptation is critically involved in cellular survival and in lifespan extension by calorie restriction.