Journal
AGING CELL
Volume 7, Issue 1, Pages 101-111Publisher
WILEY
DOI: 10.1111/j.1474-9726.2007.00357.x
Keywords
GSK3 beta; longevity; mitochondria; oxidative stress; PGC-1 alpha; SIRT1
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Funding
- NCI NIH HHS [P20 CA103697] Funding Source: Medline
- NIA NIH HHS [P01 AG11915, T32 AG00214, T32 AG000213, P01 AG011915, T32 AG000214] Funding Source: Medline
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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.
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