Regulatory mechanisms of mitochondrial cristae biogenesis and thermogenic function

线粒体嵴生物发生和产热功能的调节机制

• 批准号: 10716595
• 负责人: Pere Puigserver
• 金额: $ 69.18万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716595
• 关键词: Address; Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Agonist; Applications Grants; Biogenesis; Body Temperature; Body Weight; Calories; Clinical; Complex; Coupled; Crista ampullaris; Devices; Diet; Electron Transport; Energy Metabolism; Exercise; Exhibits; Fatty acid glycerol esters; Genetic; Goals; Health; Heart; High Fat Diet; Human; Impairment; In Vitro; Inner mitochondrial membrane; Intake; Knockout Mice; Life; Link; Malignant Neoplasms; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial Proteins; Molecular; Molecular Chaperones; Molecular Profiling; Mus; Non-Insulin-Dependent Diabetes Mellitus; OPA1 gene; Obesity; Organelles; Outcome; Outcome Study; Outer Mitochondrial Membrane; Oxygen Consumption; PERK kinase; Phenotype; Protein Import; Proteins; Protons; Reaction; Regimen; Regulation; Respiration; Respiratory physiology; Risk; Signal Transduction; Signaling Protein; Stimulus; Structure; Thermogenesis; Tubular formation; UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; Virus Diseases; Weight Gain; bariatric surgery; cold stress; cold temperature; combat; cost; cost effective treatment; diabetic; dietary; dietary control; energy balance; expectation; feeding; gain of function; glycosylation; in vivo; loss of function; mitochondrial fitness; mouse model; non-compliance; organizational structure; protein complex; respiratory; respiratory protein; response

Abstract Metabolic diseases include obesity and type 2 diabetes (T2D) are associated with exacerbated health risks that can be life threatening such as heart complications, viral infections, or cancer. Current therapies to treat obesity are based on exercise, diet, and/or bariatric surgery that not always are possible or succeed due to genetic components, non-compliance, or excessive cost. There is a need to understand the mechanisms that sustain energy balance to provide more efficient and cost-effective therapies. Activation of adaptive thermogenesis is an attractive approach to combat obesity/T2D. Increased thermogenic and metabolic function in response to lower temperatures or high calorie diets occurs, at least in part, in specialized fat cells, brown and beige adipocytes. Adult humans possess mitochondria-enriched beige-like adipocytes that display molecular signatures resembling murine beige fat and can be reactivated by cold or b3 agonists causing metabolic benefits. Thermogenic activity in specialized adipose cells depends on the fitness of mitochondrial organelles carrying uncoupling respiration or futile reactions that dissipate energy as heat. Mitochondrial respiration occurs in organized structures called cristae, tubular invaginations of the inner mitochondrial membrane that function as battery-like devices generating and dissipating energy. We have identified a new cold stress inducible mechanism that controls mitochondrial cristae assembly and thermogenic activity in brown/beige adipose cells. Components of this thermogenic regulatory mechanism include the cold- and adrenergic-activated ER resident kinase PERK that signals to mitochondrial protein import machinery facilitating assembly of MICOS complexes that organize and promote cristae biogenesis. In vitro and in vivo studies show that adipose PERK deficiency results in defective cristae formation and impaired thermogenic responses. The premise of this application is that the ER signals to the mitochondrial protein import to control cristae biogenesis and form competent thermogenic adipocytes protecting against lower temperatures and obesity/T2D. We have three aims: 1) determine the regulatory mechanisms of cristae biogenesis and thermogenic function through PERK activation, focusing on how PERK controls cristae formation including activation of OGT-dependent glycosylation; 2) determine the mechanisms of cold-dependent mitochondrial protein import coupled to thermogenic function, investigating co-chaperones and TOM70-assisted MIC19 protein import that causes cristae biogenesis and thermogenic function, and 3) analysis of mitochondrial cristae formation and metabolic/energetic function during cold- and diet-induced thermogenesis using genetic mouse models, focusing on how different this signaling ER- mitochondria axis impacts energy balance and metabolism during cold adaptation and high fat diet feeding. The outcomes of this application will determine the regulatory mechanisms that control thermogenic mitochondrial cristae biogenesis in response to lower temperatures and excess calorie intake. These regulatory mechanisms have important implications in metabolic diseases including obesity and T2D and related clinical complications.

摘要 包括肥胖和2型糖尿病（T2 D）在内的代谢性疾病与加重的健康风险相关， 可能危及生命，如心脏并发症、病毒感染或癌症。目前治疗肥胖症的疗法 基于运动，饮食和/或减肥手术，由于遗传原因，这些手术并不总是可能或成功的。 零部件、不合规或成本过高。有必要了解维持这种现象的机制， 能量平衡，以提供更有效和更具成本效益的治疗。适应性产热的激活是 一种对抗肥胖/T2 D的有吸引力的方法。增加产热和代谢功能， 低温或高热量饮食至少部分发生在棕色和米色的专门脂肪细胞中 脂肪细胞成年人拥有富含脂肪酸的米色样脂肪细胞， 类似于鼠米色脂肪的特征，并且可以被冷或B3激动剂重新激活，从而产生代谢益处。 在专门的脂肪细胞产热活动取决于健身线粒体细胞器携带 使呼吸分离或无效的反应，以热量的形式耗散能量。线粒体呼吸发生在 有组织的结构称为嵴，线粒体内膜的管状内陷，其功能是 产生和消耗能量的类似电池的装置。我们已经确定了一种新的冷应激诱导 在棕色/米色脂肪细胞中控制线粒体嵴组装和产热活动的机制。 这种产热调节机制的组成部分包括冷激活和肾上腺素能激活的ER常驻 激酶PERK，其向线粒体蛋白质输入机制发出信号，促进MICOS复合物组装 组织和促进嵴的生物发生。体外和体内研究表明，脂肪PERK缺乏 导致嵴形成缺陷和产热反应受损。这个应用的前提是 ER信号传递到线粒体蛋白质进口，以控制嵴的生物发生并形成有能力的 产热脂肪细胞保护免受低温和肥胖/T2 D。我们有三个目标：（1） 通过PERK激活确定嵴生物发生和产热功能的调节机制， 关注PERK如何控制嵴形成，包括OGT依赖性糖基化的激活; 2） 确定与产热功能偶联的冷依赖性线粒体蛋白输入的机制， 研究导致嵴生物发生的辅助分子伴侣和TOM 70辅助的MIC 19蛋白输入， 产热功能，和3）分析线粒体嵴形成和代谢/能量功能， 冷和饮食诱导的产热使用遗传小鼠模型，重点是如何不同的这种信号ER- 线粒体轴影响冷适应和高脂饮食喂养过程中的能量平衡和代谢。的 本申请的结果将确定控制产热线粒体的调节机制 嵴生物发生反应较低的温度和过量的热量摄入。这些监管机制 在包括肥胖和T2 D以及相关临床并发症的代谢疾病中具有重要意义。