Control of Mitochondrial Bioenergetic Function through the mTOR Pathway

描述（由申请人提供）：代谢综合征的几个危险因素，如胰岛素抵抗和肥胖，存在与细胞内脂质积累增加相关的线粒体功能障碍。在对营养和寒冷刺激的反应中，含有PGC-1a的转录复合物控制线粒体氧化功能以维持能量稳态。mTOR是对营养和激素信号作出反应并调节细胞生长、大小和存活的重要组成部分。然而，mTOR是否以及如何控制线粒体氧化活性尚不清楚。我们有初步的实验表明，骨骼肌中mTOR是维持线粒体氧化功能所必需的。我们已经确定转录因子YY1和辅激活因子PGC-1a通过调节它们的物理相互作用来介导mTOR线粒体效应。然而，从mTOR到YY1/PGC-1a信号转导的分子机制尚不清楚。本提案的主要目标是确定mTOR途径通过YY1/PGC-1a调节线粒体基因表达的机制，并测试其在糖尿病中的功能

DESCRIPTION (provided by applicant): Several risks factors of the metabolic syndrome such as insulin resistance and obesity present mitochondrial dysfunction that is associated with increased intramyocellular lipid accumulation. In response to nutrients and cold stimuli, transcriptional complexes that contain PGC-1a control mitochondrial oxidative function to maintain energy homeostasis. mTOR is an important component that responds to nutrient and hormonal signals and regulates cell growth, size and survival. However, whether and how mTOR controls mitochondrial oxidative activities is unknown. We have preliminary experiments indicating that in skeletal muscle mTOR is necessary to maintain mitochondrial oxidative function. We have identified that the transcription factor YY1 and the coactivator PGC-1a are mediating mTOR mitochondrial effects through modulation of their physical interaction. However, the molecular mechanisms of the signal transduction from mTOR to YY1/PGC-1a are unknown. The major goal of this proposal is to identify the mechanisms by which mTOR pathway regulates mitochondrial gene expression through the YY1/PGC-1a and to test their functionality in in-vivo mouse models. To accomplish this goal, we will use a variety of biochemical, cellular and genetic approaches. We have three aims. Aim 1 is to perform molecular and functional analysis of how mTOR controls YY1 transcriptional function. Aim 2 is to carry out molecular and functional analysis of the mTOR activity-dependent interaction between YY1 and PGC-1a. Aim 3 will determine the effects of mTOR inhibition on the metabolic and bioenergetic function in mice. This investigation will allow us to identify the molecular mechanisms by which the nutrient sensor pathway regulates YY1/PGC-1a and how defects in this pathway results in dysregulated mitochondrial function and energy balance. PUBLIC HEALTH RELEVANCE: Since mitochondrial pathways are dysregulated metabolic diseases such as obesity and type 2 diabetes, studies in this grant proposal to understand how mTOR control mitochondrial function might translate into potential therapies for these diseases.