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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的代谢疾病包括肥胖和2型糖尿病（T2D）与恶化的健康风险有关可能会威胁生命，例如心脏并发症，病毒感染或癌症。当前治疗肥胖症的疗法基于运动，饮食和/或减肥手术，并非总是可能或因遗传而成功的组件，不合规或成本过高。有必要了解维持的机制能量平衡以提供更有效和具有成本效益的疗法。自适应生热的激活是抗肥胖/T2D的有吸引力的方法。响应于较低的温度或高卡路里饮食至少在特殊的脂肪细胞（棕色和米色）中发生脂肪细胞。成年人具有线粒体富含米色的脂肪细胞，显示分子标志类似于鼠米色脂肪，可以通过寒冷或B3激动剂重新激活，从而导致代谢益处。专业脂肪细胞中的热活性取决于携带线粒体细胞器的适应性解开呼吸或徒劳的反应，将能量作为热量消散。线粒体呼吸发生在有组织的结构称为Cristae，内部线粒体膜的肾小管起伏电池状的设备产生和耗散能量。我们已经确定了一种新的冷应力诱导控制棕色/米色脂肪细胞中线粒体Cristae组装和热活性的机制。这种热调节机制的组成部分包括冷和肾上腺素能激活的ER常驻激酶perk信号向线粒体蛋白进口机械促进米奇综合体的组装组织和促进Cristae生物发生。体外和体内研究表明，脂肪Perk缺乏症导致CRISTAE形成缺陷并受损的热反应。此应用程序的前提是 ER信号向线粒体蛋白进口以控制Cristae生物发生并形成胜任可预防较低温度和肥胖/T2D的热脂肪细胞。我们有三个目标：1）通过PERK激活确定Cristae生物发生和热功能的调节机制，着重于振兴如何控制Cristae的形成，包括激活OGT依赖性糖基化； 2）确定与热功能相结合的冷依赖性线粒体蛋白的机制，研究共同伴侣和TOM70辅助MIC19蛋白导入，导致Cristae生物发生和热功能和3）分析线粒体Cristae的形成和代谢/能量功能使用遗传小鼠模型冷和饮食诱导的热发生，重点是这种信号传导如何不同线粒体轴影响冷适应过程中的能量平衡和代谢。这该应用的结果将确定控制热线粒体的调节机制 Cristae生物发生响应较低的温度和过量的卡路里摄入量。这些调节机制对包括肥胖和T2D和相关临床并发症在内的代谢疾病具有重要意义。