Control of Mitochondrial Bioenergetic Function through the mTOR Pathway

描述(申请人提供)：代谢综合征的几个风险因素，如胰岛素抵抗和肥胖，表现为线粒体功能障碍，与心肌细胞内脂质堆积增加有关。作为对营养和冷刺激的响应，含有PGC-1a的转录复合体控制线粒体的氧化功能，以维持能量平衡。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的氧化活性尚不清楚。我们有初步的实验表明，在骨骼肌中，mTOR是维持线粒体氧化功能所必需的。我们已经证实，转录因子YY1和共激活因子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，mTOR向YY1/PGC-1a信号转导的分子机制尚不清楚。本研究的主要目的是确定mTOR途径通过YY1/PGC-1a调节线粒体基因表达的机制，并测试它们在 活体小鼠模型。为了实现这一目标，我们将使用各种生化、细胞和遗传方法。我们有三个目标。目的1是对mTOR如何调控YY1转录功能进行分子和功能分析。目的2是对YY1和PGC-1a之间mTOR活性依赖的相互作用进行分子和功能分析。目的3确定mTOR抑制对小鼠代谢和生物能量功能的影响。这项研究将使我们能够确定营养传感器途径调节YY1/PGC-1a的分子机制，以及该途径的缺陷如何导致线粒体功能和能量平衡失调。公共卫生相关性：由于线粒体途径是代谢失调的疾病，如肥胖和2型糖尿病，本赠款提案中关于了解mTOR如何控制线粒体功能的研究可能会转化为这些疾病的潜在治疗方法。

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.