Defective mitochondrial morphology and bioenergetic function in mice lacking the transcription factor Yin Yang 1 in skeletal muscle.
The formation, distribution, and maintenance of functional mitochondria are achieved through dynamic processes that depend strictly on the transcription of nuclear genes encoding mitochondrial proteins. A large number of these mitochondrial genes contain binding sites for the transcription factor Yin Yang 1 (YY1) in their proximal promoters, but the physiological relevance is unknown. We report here that skeletal-muscle-specific YY1 knockout (YY1mKO) mice have severely defective mitochondrial morphology and oxidative function associated with exercise intolerance, signs of mitochondrial myopathy, and short stature. Gene set enrichment analysis (GSEA) revealed that the top pathways downregulated in YY1mKO mice were assigned to key metabolic and regulatory mitochondrial genes. This analysis was consistent with a profound decrease in the level of mitochondrial proteins and oxidative phosphorylation (OXPHOS) bioenergetic function in these mice. In contrast to the finding for wild-type mice, inactivation of the mammalian target of rapamycin (mTOR) did not suppress mitochondrial genes in YY1mKO mice. Mechanistically, mTOR-dependent phosphorylation of YY1 resulted in a strong interaction between YY1 and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), a major regulator of mitochondrial function. These results underscore the important role of YY1 in the maintenance of mitochondrial function and explain how its inactivation might contribute to exercise intolerance and mitochondrial myopathies.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Sharon M
SM
Blättler
Francisco
F
Verdeguer
Marc
M
Liesa
John T
JT
Cunningham
Rutger O
RO
Vogel
Helen
H
Chim
Huifei
H
Liu
Klaas
K
Romanino
Orian S
OS
Shirihai
Francisca
F
Vazquez
Markus A
MA
Rüegg
Yang
Y
Shi
Pere
P
Puigserver
D000483:Alleles; D000818:Animals; D004734:Energy Metabolism / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010641:Phenotype; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000235:genetics* / Q000502:physiology
D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases