Exercise Increases Mitochondrial PGC-1α Content and Promotes Nuclear-Mitochondrial Cross-talk to Coordinate Mitochondrial Biogenesis (Publication with Expression of Concern. See vol. 293, pg. 4953, 2018) (Withdrawn Publication. See vol. 295, pg. 17888, 2020)

Endurance exercise is known to induce metabolic adaptations in skeletal muscle via activation of the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1 alpha). PGC-1 alpha regulates mitochondrial biogenesis via regulating transcription of nuclear-encoded mitochondrial genes. Recently, PGC-1 alpha has been shown to reside in mitochondria; however, the physiological consequences of mitochondrial PGC-1 alpha remain unknown. We sought to delineate if an acute bout of endurance exercise can mediate an increase in mitochondrial PGC-1 alpha content where it may co-activate mitochondrial transcription factor A to promote mtDNA transcription. C57Bl/6J mice (n = 12/group; female = male) 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-1 alpha in END and END + 3h groups was significantly higher versus SED mice. In mitochondria, PGC-1 alpha 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-1 alpha at the NRF-1 promoter. We conclude that in response to acute altered energy demands, PGC-1 alpha 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-1 alpha may dynamically facilitate nuclear-mitochondrial DNA cross-talk to promote net mitochondrial biogenesis.