Transcriptional Control of Mitochondrial Bioenergetic Function

线粒体生物能功能的转录控制

• 批准号: 8502055
• 负责人: Pere Puigserver
• 金额: $ 38.99万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502055
• 关键词: Accounting; Adipocytes; Adipose tissue; Adrenergic Agents; Affect; Amino Acids; Animals; Applications Grants; Atherosclerosis; Automobile Driving; Biochemical; Biochemical Process; Bioenergetics; Body Weight; Brown Fat; Cells; Complex; Cultured Cells; Cyclic AMP; Defect; Diabetes Mellitus; Diet; Disease; Energy Intake; Energy Metabolism; Equilibrium; Family; Fatty acid glycerol esters; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Heating; Homeostasis; Investigation; Laboratories; Maintenance; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial Proteins; Molecular; Molecular Analysis; Mus; Muscle Cells; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Hormone Receptors; Nutrient; Obesity; Outcome Study; Pathway interactions; Phosphorylation; Polycomb; Preparation; Process; Proteins; Recruitment Activity; Regulation; Repressor Proteins; Respiration; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; System; Testing; Tissues; Transcription Coactivator; Transcriptional Regulation; Translating; Work; YY1 Transcription Factor; adrenergic; base; chromatin protein; energy balance; feeding; gain of function; glucose metabolism; in vivo; lipid metabolism; loss of function; metabolomics; mouse model; nuclear respiratory factor; oxidation; protein complex; protein expression; public health relevance; research study; scaffold; skeletal

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.

描述（由适用提供）：能量消耗（体重的主要组成部分）是通过控制生物能/代谢功能的信号传导和转录组件形成的复杂调节网络来调节的。骨骼肌和米色/棕色脂肪是关键组织，其占能量消耗的一部分。肾上腺素/cAMP信号传导是影响能量平衡和细胞生物能学的强大途径之一。信号/转录和线粒体生物能系统组成部分的缺陷足以促进肥胖和相关疾病，例如2型糖尿病和动脉粥样硬化。重要的是，线粒体生物能功能的维持和激活严格取决于编码线粒体蛋白的核基因的基本和调节转录。在这些线粒体过程的转录调节剂中，有共激活因子和转录因子的PGC1家族，包括核呼吸因子，激素核受体和YY1。在过去的几年中，我们的实验室将转录因子YY1确定为核线粒体基因的关键调节剂，在培养的细胞和动物中，对线粒体生物能力产生了重大影响。根据特定部位的YY1磷酸化，磷酸YY1通过募集PGC1募集在线粒体基因上形成活跃的复合物。相比之下，Dephospho-Yy1通过与抑制线粒体基因表达的多角膜蛋白相互作用而形成了复制复合物。重要的是，依赖YY1依赖的光磷酸化相互作用的信号之一是cAMP通路。基于这些发现，该提案的主要目标是通过YY1转录复合物确定驱动线粒体基因表达的调节机制，并使用肥胖和糖尿病的体内小鼠模型评估功能。我们有三个特定的目的：目标1提案，以对YY1转录复合物如何控制线粒体功能进行分子机械分析。 AIM 2致力于在骨骼和脂肪培养的细胞中介导的细胞和功能性线粒体生物能和代谢分析。 AIM 3专注于进行体内代谢和能量分析，该分析是由骨骼肌和脂肪组织中的YY1转录因子介导的。我们将使用这些组织中具有YY1功能的遗传小鼠模型。这些研究的结果将提供分子机制的鉴定，YY1转录复合物调节线粒体生物能力的能力以及该复合物中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症和糖尿病等代谢疾病中改变的事实，该赠款应用中提出的研究可能会转化为潜在的疗法。