Transcriptional Control of Mitochondrial Bioenergetic Function

描述（由申请人提供）：能量消耗（体重的主要组成部分）通过一个复杂的调节网络进行调节，该网络由控制生物能量/代谢功能的信号和转录成分组成。骨骼肌和米色/棕色脂肪是消耗大部分能量的关键组织。肾上腺素能/cAMP信号是影响能量平衡和细胞生物能量学的重要途径之一。信号/转录和线粒体生物能量系统成分的缺陷足以促进肥胖和相关疾病，如2型糖尿病和动脉粥样硬化。重要的是，线粒体生物能量功能的维持和激活严格依赖于编码线粒体蛋白的核基因的基础和调控转录。这些线粒体过程的转录调节因子包括PGC1家族的共激活因子和转录因子，包括核呼吸因子、激素核受体和YY1。在过去的几年中，我们的实验室已经确定转录因子YY1作为核线粒体基因的关键调节因子，在培养细胞和动物中对线粒体生物能量能力有重大影响。根据YY1在特定位点的磷酸化，phospho-YY1通过募集PGC1在线粒体基因上形成一个活性复合物。相反，dephospho-YY1通过与Polycomb蛋白相互作用形成抑制复合物，抑制线粒体基因的表达。重要的是，控制yy1依赖性磷酸化相互作用的信号之一是cAMP途径。基于这些发现，本提案的主要目标是确定通过YY1转录复合物驱动线粒体基因表达的调控机制，并使用肥胖和糖尿病小鼠模型评估其功能。我们有三个具体目标：目标1提出对YY1转录复合体如何控制线粒体功能进行分子机制分析。Aim 2致力于在骨骼和脂肪培养细胞中进行由YY1转录蛋白复合物介导的细胞和功能性线粒体生物能量和代谢分析。Aim 3的重点是在骨骼肌和脂肪组织中进行由YY1转录因子介导的体内代谢和能量分析。我们将使用在这些组织中获得和失去YY1功能的遗传小鼠模型。这些研究的结果将提供YY1转录复合体调节线粒体生物能量能力的分子机制，以及该复合体的缺陷如何导致线粒体功能和能量平衡失调。基于这些途径在代谢疾病（如肥胖和糖尿病）中发生改变的事实，本资助申请中提出的研究可能转化为潜在的治疗方法。

DESCRIPTION (provided by applicant): Energy expenditure (a major component of body weight) is regulated through a complex regulatory network formed by signaling and transcriptional components that control bioenergetic/metabolic function. Skeletal muscle and beige/brown adipose are key tissues that account for a large fraction of energy expenditure. Adrenergic/cAMP signaling is one of the powerful pathways that affect energy balance and cellular bioenergetics. Defects in components of the signaling/transcriptional and mitochondrial bioenergetic system is sufficient to promote obesity and associated disorders such as type 2 diabetes and atherosclerosis. Importantly, maintenance and activation of mitochondrial bioenergetic function strictly depend on basal and regulated transcription of nuclear genes encoding for mitochondrial proteins. Among the transcriptional regulators of these mitochondrial processes are the PGC1 family of coactivators and transcription factors including Nuclear Respiratory Factors, Hormone Nuclear Receptors and YY1. In the last years, our laboratory has identified the transcription factor YY1 as a key regulator of nuclear mitochondrial genes that has a major impact in mitochondrial bioenergetic capacity, both in cultured cells and in animals. Depending on YY1 phosphorylation at specific sites, phospho-YY1 forms an active complex on mitochondrial genes through recruitment of PGC1�. In contrast, dephospho-YY1 forms a repressor complex through interacting with Polycomb Proteins that suppresses the expression of mitochondrial genes. Importantly, one of the signals that govern YY1-dependent phosphorylation interaction is the cAMP pathway. Based on these findings, the major goal of this proposal is to identify the regulatory mechanisms driving mitochondrial gene expression through YY1 transcriptional complex and to assess the functionality using in-vivo mouse models of obesity and diabetes. We have three Specific Aims: Aim 1 proposes to perform molecular mechanistic analysis of how the YY1 transcriptional complex controls mitochondrial function. Aim 2 is devoted to carry out cellular and functional mitochondrial bioenergetic and metabolic analysis mediated by the YY1 transcriptional protein complex in skeletal and adipose cultured cells. Aim 3 is focused to perform in-vivo metabolic and energetic analysis mediated by the YY1 transcription factor in skeletal muscle and adipose tissues. We will use genetic mouse models with gain and loss-of-function of YY1 in these tissues. The outcomes of these studies will provide the identification of the molecular mechanisms by which the YY1 transcriptional complex regulates mitochondrial bioenergetic capacities and how defects in this complex result in dysregulated mitochondrial function and energy balance. Based on the fact that these pathways are altered in metabolic diseases such as obesity and diabetes, studies proposed in this grant application might translate into potential therapies.