Mechanisms of mitochondrial-ER communication during dietary and thermal induced stress

饮食和热应激期间线粒体-内质网通讯的机制

• 批准号: 10663603
• 负责人: Pedro Antonio Latorre Muro
• 金额: $ 9万
• 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: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663603
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Affect; Amino Acids; Award; Binding; Biochemical; Bioenergetics; Biogenesis; Blood Glucose; Body Weight; CRISPR/Cas technology; Cardiovascular Diseases; Cell Respiration; Cell physiology; Cellular biology; Client; Collaborations; Communication; Communities; Complex; Country; Crista ampullaris; Cryoelectron Microscopy; Dana-Farber Cancer Institute; Data; Development; Development Plans; Diabetes Mellitus; Diet; Disease; Endoplasmic Reticulum; Energy Metabolism; Ensure; Environment; Epidemic; Equilibrium; Event; Exercise; Experimental Designs; Exposure to; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Future; Glucose; Goals; Health; Heat-Shock Proteins 70; Heat-Shock Proteins 90; High Fat Diet; Homeostasis; In Vitro; Individual; Inflammation; Institution; Insulin Resistance; Knockout Mice; Knowledge; Laboratories; Liver; Long-Term Effects; LoxP-flanked allele; Malignant Neoplasms; Manuscripts; Mass Spectrum Analysis; Membrane; Mentorship; Metabolic Diseases; Metabolism; Microscope; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Molecular Chaperones; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Nuclear Proteins; Obesity; Organ; Organelles; Outcome; PERK kinase; Pathway interactions; Phase; Physiology; Population; Preparation; Protein Import; Protein Precursors; Receptor Signaling; Regulation; Regulatory Element; Research; Research Personnel; Risk; Role; SARS-CoV-2 infection; Sampling; Shapes; Signal Pathway; Signal Transduction; Skeletal Muscle; Stress; Students; Thermogenesis; Training; Weight Gain; Work; acid stress; age related; blood glucose regulation; bone; career development; diet-induced obesity; dietary; dietary control; energy balance; fatty acid oxidation; follow-up; improved; in vivo; insulin sensitivity; medical schools; mouse model; novel; novel therapeutic intervention; pandemic disease; protein complex; protein function; research and development; response; skills; stressor; structural biology; sugar; therapeutic target; thermal stress; tool

Project Summary/Abstract Obesity is a pandemic affecting 40% of the population that increases the risk of serious metabolic diseases including type 2 diabetes and severe forms of SARS-CoV2 infection. Obesity reduces insulin sensitivity and dysregulates glucose homeostasis sustaining high blood glucose levels and the development of type 2 diabetes. Activation of brown adipocytes (BAs) is a promising approach to treat obesity and associated diseases. Brown adipocytes rely on an extensive network of mitochondria that increases energy expenditure and maintains glucose homeostasis through glucose, amino acid, and fatty acid oxidation. During fat-induced stress, mitochondrial-endoplasmic reticulum (ER) communication sustains cellular function in BAs. However, the mechanisms by which mitochondrial-ER communication shapes cellular adaptation during obesity are poorly understood. Therefore, studying these pathways will provide new therapeutical approaches to target obesity. The main goal of this application is to study the mechanisms of mitochondrial-ER communication that ensure mitochondrial function and cellular homeostasis during diet-induced stress. We have described that in BAs mitochondrial-ER communication promotes thermogenesis during cold stimulation through the ER-resident kinase PERK. To follow up this work, in Aim 1, the effects of long-term high fat diet (HFD) will be studied in UCP1-Cre PERK-/- mice exposed to different dietary and bioenergetic conditions. Our preliminary information suggests that PERK may be signaling to the chaperone PPID to control mitochondrial protein import. In Aim 2, structural approaches using Cryogenic Electron Microscopy (CryoEM) will be used to explore the molecular interactions that control and maintain mitochondrial functions in BAs including mitochondrial protein import, focusing on PPID-dependent pathway, and cellular respiration during dietary and thermal stress. Finally, in Aim 3 the role of PPID in physiology and cellular functions will be studied in mice exposed to diet and thermal stress. While Aims 1 and part of 2 will be completed during the training stage, part of Aim 2 and the entire Aim 3 will be conducted during the independent phase of the award. The extensive training in different fields proposed in this application including physiology and cellular and structural biology will provide the tools to become an independent researcher and study the mechanisms of inter- organalle communication that regulate mitochondrial biogenesis and cellular metabolism. This training will be received in the vibrant scientific communities of Dana-Farber Cancer Institute and Harvard Medical School. This environment will expose me to the collaborations and discussions necessary for career development and future opportunities. Dr. Puigserver mentorship will be supportive to establish those connections and actively guide me in talk and manuscript preparation, student mentorship, experimental design, and career development. Together, the research and career development plans proposed in this application will strengthen my skills and competitiveness to become an independent researcher at a major institution.

项目总结/文摘