Dynamic regulation of PGC-1α 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 1 alpha (PGC-1 alpha). We demonstrate that PGC-1 alpha subcellular distribution is regulated, and its transcriptional activity is promoted through SIRT1-dependent nuclear accumulation. In addition, the duration of PGC-1 alpha activity is regulated by glycogen synthase kinase beta (GSK3 beta), which targets PGC-1 alpha for intranuclear proteasomal degradation. This mechanism of regulation permits the rapidity and persistence of PGC-1 alpha activation to be independently controlled. We provide evidence that this pathway of PGC-1 alpha 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.