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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.

项目总结/文摘