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.

抽象的肥胖和 2 型糖尿病 (T2D) 等代谢疾病与加剧的健康风险相关，可能会危及生命，例如心脏并发症、病毒感染或癌症。目前治疗肥胖的疗法基于运动、饮食和/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。需要了解维持的机制能量平衡以提供更有效和更具成本效益的治疗。适应性生热作用的激活是对抗肥胖/T2D 的一种有吸引力的方法。增加生热和代谢功能以应对较低的温度或高热量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。成年人拥有富含线粒体的米色样脂肪细胞，显示分子特征类似于小鼠米色脂肪，可以通过寒冷或 B3 激动剂重新激活，从而产生代谢益处。特殊脂肪细胞的产热活性取决于线粒体细胞器的适应性解耦呼吸或以热量形式耗散能量的无用反应。线粒体呼吸发生在称为嵴的组织结构，线粒体内膜的管状内陷，其功能如下类似电池的设备产生和消耗能量。我们发现了一种新的冷应激诱导剂控制棕色/米色脂肪细胞中线粒体嵴组装和产热活性的机制。这种产热调节机制的组成部分包括冷激活和肾上腺素激活的 ER 驻留蛋白。激酶 PERK 向线粒体蛋白输入机制发出信号，促进 MICOS 复合物的组装组织和促进嵴生物发生。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。本申请的前提是 ER向线粒体蛋白输入发出信号以控制嵴生物发生并形成感受态产热脂肪细胞可防止低温和肥胖/T2D。我们有三个目标：1）通过 PERK 激活确定嵴生物发生和生热功能的调节机制，重点关注 PERK 如何控制嵴形成，包括 OGT 依赖性糖基化的激活； 2）确定冷依赖性线粒体蛋白输入与产热功能耦合的机制，研究导致嵴生物发生的共伴侣和 TOM70 辅助的 MIC19 蛋白输入产热功能，3) 线粒体嵴形成和代谢/能量功能分析使用遗传小鼠模型研究寒冷和饮食诱导的生热作用，重点关注这种信号 ER- 线粒体轴影响寒冷适应和高脂肪饮食喂养期间的能量平衡和新陈代谢。这该应用的结果将确定控制产热线粒体的调节机制嵴生物发生响应较低的温度和过量的卡路里摄入。这些监管机制对肥胖和 T2D 等代谢疾病以及相关临床并发症具有重要意义。