Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1

Mitochondrial number and function are altered in response to external stimu li in eukaryotes. While several transcription/replication factors directly regulate mitochondrial genes, the coordination of these factors into a prog ram responsive to the environment is not understood. We show here that PGC- 1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondr ial biogenesis and respiration in muscle cells through an induction of unco upling protein 2 (UCP-2) and through regulation of the nuclear respiratory factors (NRFs). PGC-1 stimulates a powerful induction of NRF-1 and NRF-5 ge ne expression; in addition, PGC-1 binds to and coactivates the transcriptio nal function of NRF-1 on the promoter for mitochondrial transcription facto r A (mtTFA), a direct regulator of mitochondrial DNA replication/transcript ion. These data elucidate a pathway that directly links external physiologi cal stimuli to the regulation of mitochondrial biogenesis and function.