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）通过控制生物能量/代谢功能的信号传导和转录组分形成的复杂调控网络进行调控。骨骼肌和米色/棕色脂肪是占能量消耗很大一部分的关键组织。肾上腺素能/cAMP信号传导是影响能量平衡和细胞生物能量学的强大途径之一。信号传导/转录和线粒体生物能量系统的组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质的核基因的基础和调节转录。这些线粒体过程的转录调节因子包括PGC 1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YY 1。在过去的几年中，我们的实验室已经确定了转录因子YY 1作为核线粒体基因的关键调节因子，其在培养细胞和动物中对线粒体生物能量能力具有重大影响。根据YY 1在特定位点的磷酸化，磷酸-YY 1通过募集PGC 1？在线粒体基因上形成活性复合物。相反，去磷酸-YY 1通过与多梳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YY 1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YY 1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的体内小鼠模型评估其功能。我们有三个具体目标：目的1提出对YY 1转录复合体如何控制线粒体功能进行分子机制分析。目的二是研究YY 1转录蛋白复合体介导的骨骼肌和脂肪细胞线粒体的细胞和功能的能量代谢。目的3是进行骨骼肌和脂肪组织中YY 1转录因子介导的体内代谢和能量分析。我们将使用这些组织中YY 1功能获得和丧失的遗传小鼠模型。这些研究的结果将提供YY 1转录复合物调节线粒体生物能量能力的分子机制的鉴定，以及该复合物的缺陷如何导致线粒体功能和能量平衡失调。基于这些途径在肥胖和糖尿病等代谢疾病中发生改变的事实，这项拨款申请中提出的研究可能会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.