mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex

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Abstract
The nutrient sensor molecule mTOR (mammalian target of rapamycin) is a kinase involved in the regulation of cell growth and proliferation. Its close links to the cell's energetics suggest that it might interact with the mitochondria, and a computational genomics study now confirms that it does. mTOR balances energy metabolism via transcriptional control of mitochondrial gene expression and oxidative function, with the transcriptional regulators PGC-1a and YY1 as mediators. This pathway opens new possibilities for therapeutic interventions in metabolic diseases in which mitochondrial activity is compromised. The nutrient sensor mTOR controls mitochondrial gene expression and oxidative function via an interaction between the transcriptional regulators PGC-1α and YY1. Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1α control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals1,2. An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival3,4,5. However, it is unknown whether and how mTOR controls mitochondrial oxidative activities. Here we show that mTOR is necessary for the maintenance of mitochondrial oxidative function. In skeletal muscle tissues and cells, the mTOR inhibitor rapamycin decreased the gene expression of the mitochondrial transcriptional regulators PGC-1α, oestrogen-related receptor α and nuclear respiratory factors, resulting in a decrease in mitochondrial gene expression and oxygen consumption. Using computational genomics, we identified the transcription factor yin-yang 1 (YY1) as a common target of mTOR and PGC-1α. Knockdown of YY1 caused a significant decrease in mitochondrial gene expression and in respiration, and YY1 was required for rapamycin-dependent repression of those genes. Moreover, mTOR and raptor interacted with YY1, and inhibition of mTOR resulted in a failure of YY1 to interact with and be coactivated by PGC-1α. We have therefore identified a mechanism by which a nutrient sensor (mTOR) balances energy metabolism by means of the transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer.