| Regulation of mitochondrial biogenesis and function involves a finely tuned process that is controlled by a transcriptional program coordinated by multiple pathways that signal to transcription factors and cofactors. Dysregulation of this transcriptional program leads to mitochondrial dysfunction which can result in metabolic disorders such as type 2 diabetes and obesity as well as pathological conditions such as aging. The mTOR pathway is known to respond to a variety of environmental stimuli such as growth factors and nutrients in order to orchestrate downstream signaling events leading to cell growth, proliferation, and cell survival. However, little is known regarding how mTOR controls the changes in cellular metabolism that are necessary to undergo such energy-consuming processes. We show here that mTOR positively regulates mitochondrial function and biogenesis in skeletal muscle and C2C12 myotubes through controlling transcription of nuclear-encoded mitochondrial genes. We utilized a computational genomics approach to identify the transcription factor YY1 as the downstream effector of the mTOR pathway. We show that mTOR controls YY1 by modulating the interaction between YY1 and its transcriptional cofactors, PGC-1alpha and PC2. mTOR activity leads to binding of YY1 to the coact valor, PGC-1alpha, whereas inactivation of mTOR results in dissociation of PGC-1alpha concomitant with recruitment of the corepressor, PC2. Recruitment of PC2 leads to epigenetic changes in YY1 target genes that persist in aged muscle. |
