Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.
Mitochondrial number and function are altered in response to external stimuli in eukaryotes. While several transcription/replication factors directly regulate mitochondrial genes, the coordination of these factors into a program responsive to the environment is not understood. We show here that PGC-1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling protein 2 (UCP-2) and through regulation of the nuclear respiratory factors (NRFs). PGC-1 stimulates a powerful induction of NRF-1 and NRF-2 gene expression; in addition, PGC-1 binds to and coactivates the transcriptional function of NRF-1 on the promoter for mitochondrial transcription factor A (mtTFA), a direct regulator of mitochondrial DNA replication/transcription. These data elucidate a pathway that directly links external physiological stimuli to the regulation of mitochondrial biogenesis and function.
Dana-Farber Cancer Institute, and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Z
Z
Wu
P
P
Puigserver
U
U
Andersson
C
C
Zhang
G
G
Adelmant
V
V
Mootha
A
A
Troy
S
S
Cinti
B
B
Lowell
R C
RC
Scarpulla
B M
BM
Spiegelman
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051268:GA-Binding Protein Transcription Factor; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D007473:Ion Channels; D026901:Membrane Transport Proteins; D051379:Mice; D008931:Mitochondria, Muscle / Q000502:physiology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins; D008954:Models, Biological; D051265:NF-E2-Related Factor 1; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D010101:Oxygen Consumption; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000071246:Uncoupling Protein 2
D004268:DNA-Binding Proteins; D051268:GA-Binding Protein Transcription Factor; D006360:Heat-Shock Proteins; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D051265:NF-E2-Related Factor 1; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D011506:Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1