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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.

摘要