Exercise increases mitochondrial PGC-1alpha content and promotes nuclear-mitochondrial cross-talk to coordinate mitochondrial biogenesis.
Endurance exercise is known to induce metabolic adaptations in skeletal muscle via activation of the transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α). PGC-1α regulates mitochondrial biogenesis via regulating transcription of nuclear-encoded mitochondrial genes. Recently, PGC-1α has been shown to reside in mitochondria; however, the physiological consequences of mitochondrial PGC-1α remain unknown. We sought to delineate if an acute bout of endurance exercise can mediate an increase in mitochondrial PGC-1α content where it may co-activate mitochondrial transcription factor A to promote mtDNA transcription. C57Bl/6J mice (n = 12/group; ♀ = ♂) were randomly assigned to sedentary (SED), forced-endurance (END) exercise (15 m/min for 90 min), or forced endurance +3 h of recovery (END+3h) group. The END group was sacrificed immediately after exercise, whereas the SED and END+3h groups were euthanized 3 h after acute exercise. Acute exercise coordinately increased the mRNA expression of nuclear and mitochondrial DNA-encoded mitochondrial transcripts. Nuclear and mitochondrial abundance of PGC-1α in END and END+3h groups was significantly higher versus SED mice. In mitochondria, PGC-1α is in a complex with mitochondrial transcription factor A at mtDNA D-loop, and this interaction was positively modulated by exercise, similar to the increased binding of PGC-1α at the NRF-1 promoter. We conclude that in response to acute altered energy demands, PGC-1α re-localizes into nuclear and mitochondrial compartments where it functions as a transcriptional co-activator for both nuclear and mitochondrial DNA transcription factors. These results suggest that PGC-1α may dynamically facilitate nuclear-mitochondrial DNA cross-talk to promote net mitochondrial biogenesis.
Department of Kinesiology, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
Adeel
A
Safdar
Jonathan P
JP
Little
Andrew J
AJ
Stokl
Bart P
BP
Hettinga
Mahmood
M
Akhtar
Mark A
MA
Tarnopolsky
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000096:biosynthesis / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D010807:Physical Endurance / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C422562:mitochondrial transcription factor A
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