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(T2D)在内的代谢性疾病与加剧的健康风险有关 可能危及生命，如心脏并发症、病毒感染或癌症。目前治疗肥胖症的方法 是基于锻炼、节食和/或减肥手术，但由于遗传因素，这些手术并不总是可能或成功的 组件、不合规或成本过高。有必要了解维持经济增长的机制 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 对抗肥胖的有吸引力的方法/T2D。增加产热和代谢功能以应对 温度较低或热量较高的饮食至少部分发生在棕色和米色的特殊脂肪细胞中。 脂肪细胞。成年人拥有线粒体丰富的米黄色脂肪细胞，这些脂肪细胞显示出分子 类似小鼠米色脂肪的特征，可以被寒冷或b3激动剂重新激活，从而对新陈代谢有利。 特殊脂肪细胞的生热活性取决于线粒体细胞器携带的适合性 解偶联呼吸作用或将能量消耗为热的徒劳反应。线粒体呼吸作用发生在 线粒体膜内侧的有组织的结构，称为脊，即管状凹陷，其功能是 类似电池的装置，产生和耗散能量。我们发现了一种新的冷应激诱因 控制棕色/米色脂肪细胞线粒体隆起组装和生热活性的机制。 这种生热调节机制的组成部分包括冷激活和肾上腺素能激活的内质网驻留 向线粒体蛋白输入机制发出信号，促进MICOS复合体的组装 来组织和促进脊骨的生物发生。体外和体内研究表明，脂肪增高症 导致有缺陷的眉骨形成和受累的生热反应。这个应用的前提是 内质网信号转导线粒体蛋白输入调控脊的生物发生和形成 生热脂肪细胞保护免受低温和肥胖/T2D。我们有三个目标：1) 通过激活PERK确定脊骨生物发生和生热功能的调控机制， 重点研究PERK如何控制鸡冠状突起的形成，包括激活OGT依赖的糖基化；2) 确定依赖冷的线粒体蛋白输入与生热功能耦合的机制， 研究辅伴蛋白和TOM70辅助的MIC19蛋白导入导致眉骨生物发生和 生热功能；3)线粒体脊形成和代谢/能量功能分析。 利用遗传小鼠模型研究寒冷和饮食诱导的生热作用，重点研究这种信号转导机制的不同。 线粒体轴在冷适应和高脂饮食过程中影响能量平衡和代谢。这个 这一应用的结果将决定控制产热线粒体的调节机制 对较低温度和过量卡路里摄取作出反应的鸡冠生物发生。这些监管机制 对包括肥胖和T2D在内的代谢性疾病以及相关的临床并发症具有重要意义。