Mechanisms of Mitochondrial Degradation in Unstressed Mammalian Cells

无应激哺乳动物细胞线粒体降解机制

基本信息

批准号：
10401249
负责人：
MONDIRA KUNDU
金额：
$ 37.7万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-10 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401249
关键词：
Address Adipocytes Anabolism Apoptosis BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like Biochemical Biogenesis Biological Assay Biological Process Cell physiology Cells Coupled Critical Pathways Dangerousness Data Degenerative Disorder Degradation Pathway Development Disease Erythrocytes Etiology Eukaryotic Cell Foundations Genes Genetic Genetic Techniques Goals Health Health Promotion Homeostasis Human Impairment Inflammatory Life Lysosomes MAPK7 gene Mammalian Cell Mediating Metabolic Microscopy Mitochondria Molecular Molecular Genetics Mus Mutation Myopathy Neurodegenerative Disorders PINK1 gene Parkin Pathway interactions Peptide Hydrolases Pharmacology Phosphotransferases Physiological Play Process Production Proteins Proteomics Quality Control Regulation Research Resistance Reticulocytes Role Series Signal Transduction Signal Transduction Pathway Source Stimulus Stress Structure Testing Therapeutic Tissues Vesicle Work age related base bone cell injury dopaminergic neuron experimental study gene product human disease improved innovation insight macromolecule mouse genetics multicatalytic endopeptidase complex oxidative damage receptor response screening

项目摘要

Project Summary/Abstract Mitochondria play essential roles in energy production and biosynthesis of a subset of macromolecules necessary for eukaryotic life. They also house potentially dangerous intracellular machinery capable of generating oxidative damage, triggering inflammatory signaling, and initiating programmed cell death. Mitochondrial homeostasis is critical for maintaining a healthy pool of metabolically active mitochondria and avoiding cellular damage caused by the accumulation of deteriorating mitochondria. One key component of mitochondrial homeostasis is the selective degradation of old, damaged, or superfluous mitochondria. Recent efforts have elucidated in great detail the molecular mechanisms through which experimentally damaged mitochondria are degraded in Parkin-expressing eukaryotic cells. However, it is clear that mammalian cells also undergo constant renewal of mitochondrial content through biogenesis of new mitochondria coupled to degradation of old mitochondria, even in the absence of exogenous damage. The mechanisms controlling this ongoing mitochondrial turnover are poorly understood. This proposal aims to illuminate the signal transduction pathway that drives mitochondrial degradation in unstressed mammalian cells, and to use this pathway as an entry point to understand the roles that basal mitochondrial degradation plays in cellular adaptation and stress resistance. This will be accomplished by answering three key questions: 1) What controls the rate of mitochondrial turnover in the absence of exogenous damage? 2) In the absence of exogenous damage, how are mitochondria selected for degradation? 3) What role does this pathway play in developmentally programmed mitochondrial clearance? These questions will be answered using molecular and genetic techniques on the biochemical, cellular, and organismal scales. Answering these questions will provide substantial insights into the mechanistic details and physiological roles of a fundamental cell biological process. This work will improve understanding of normal development and homeostasis as well as the etiologies of diverse human diseases against which mitochondrial homeostasis protects.

项目摘要/摘要线粒体在能量生产和生物合成中起重要作用真核生活所必需的。他们还容纳了潜在危险的细胞内机械产生氧化损伤，触发炎症信号传导并引发程序性细胞死亡。线粒体稳态对于维持健康的活性线粒体和健康池至关重要避免因线粒体恶化而导致的细胞损伤。一个关键组成线粒体稳态是旧，受损或多余的线粒体的选择性降解。最近的努力详细阐明了通过实验损坏的分子机制线粒体在表达Parkin的真核细胞中降解。但是，很明显，哺乳动物细胞也通过新线粒体的生物发生对线粒体含量进行恒定更新即使在没有外源损害的情况下，旧线粒体的降解也是如此。控制这一点的机制持续的线粒体周转率了解不足。该建议旨在照亮信号转导驱动无重哺乳动物细胞中线粒体降解的途径，并将此途径用作了解基础线粒体降解在细胞适应和应力中起作用的作用的切入点反抗。这将通过回答三个关键问题来完成：1）什么控制速率在没有外源性损害的情况下，线粒体周转？ 2）在没有外源性损害的情况下线粒体是否选择降解？ 3）该途径在发育编程中起什么作用线粒体间隙？这些问题将使用分子和遗传技术在生化，细胞和生物尺度。回答这些问题将提供大量的见解基本细胞生物学过程的机械细节和生理作用。这项工作将有所改善了解正常发展和稳态以及多种人类疾病的病因线粒体体内平衡保护。