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Dissecting mechanisms of mitochondiral extrusion from C. elegans neurons

剖析线虫神经元线粒体挤出的机制

基本信息

批准号：
9462368
负责人：
MONICA A. DRISCOLL
金额：
$ 23.25万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9462368
关键词：
Address Adult Age Age-associated memory impairment Aging Alzheimer&apos s Disease Animal Model Autophagocytosis Back Behavioral Biochemical Biological Assay Biology Brain Caenorhabditis elegans Calcium Cells Data Disease Dissection Documentation Emergency Situation Equilibrium Event Exhibits Experimental Models Frequencies Functional disorder Genes Genetic Goals Health Hereditary Disease Homeostasis Human Impairment Individual Label Life Maintenance Measures Mediating Metabolism Mitochondria Mitochondrial Matrix Modeling Molecular Chaperones Morphology Mus Nervous system structure Neurodegenerative Disorders Neuroglia Neurons Organelles Oxides Oxygen Paraquat Pathway interactions Play Population Prevalence Process Production Proteins Publishing Quality Control Reporter Reporting Retinal Ganglion Cells Role Rotenone Signal Transduction Stress Stress Tests System Testing Time Touch sensation Vesicle Work aging brain fascinate in vivo in vivo calcium imaging insight medical schools mitochondrial dysfunction multicatalytic endopeptidase complex neuronal cell body neurotoxic novel novel therapeutics oxidation polyglutamine prevent protein aggregate proteostasis receptor response young adult

项目摘要

Mitochondria perform central roles in neuronal energy production, metabolism, calcium balance and ROS signaling. The maintenance of mitochondrial health and function is indisputably critical--mitochondrial dysfunction contributes to age-associated cognitive decline and multiple neurodegenerative disorders. As such, understanding mechanisms by which neurons accomplish mitochondrial quality control is a critical goal for human health. Old or damaged mitochondria are eliminated from neurons by a process called mitophagy, which recognizes and degrades them within the neuron. We have discovered a new, and previously unknown feature of young adult C. elegans neurons--neurons can selectively throw out packets of cellular contents that can include aggregated human neurodegenerative disease proteins and/or oxidized mitochondria. Remarkably, a similar phenomenon has recently been reported in mouse brain for remote degradation of mitochondria, suggesting mito-extrusion may be a conserved component of mitochondrial quality control. We have observed that genetic impairment of mitochondrial function can increase the number of extrusion events, suggesting that dysfunctional mitochondrial might be specifically thrown out. We propose that the neuronal extrusion phenomenon constitutes a significant but currently unknown pathway by which healthy neurons maintain their functions by ridding themselves of dysfunctional mitochondria--throwing out trash, rather than degrading it onsite. We will use the powerful C. elegans model in which we can readily manipulate genes and use fluorescent reporters to track mitochondria in vivo in individual neurons to address two key initial questions about mitochondrial extrusion: 1) what types of mitochondrial dysfunction are associated with increased extrusion (ROS, fission/fusion, mitophagy impairment)?, and 2) do neurons that extrude mitochondria exhibit features of healthier aging than those that do not? ! We speculate that the neuronal trash extrusion mechanism is conserved and the dysfunction of this pathway may contribute to neuronal decline in disease and aging. Mechanistic dissection of the basic biology in a facile experimental model will provide considerable insight into a process relevant to human brain aging and neurodegenerative disease, possibly inspiring new therapies. !

线粒体在神经元能量产生、代谢、钙平衡和ROS中发挥核心作用