Dissecting mechanisms of mitochondiral extrusion from C. elegans neurons

剖析线虫神经元线粒体挤出的机制

• 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
• 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' 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

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中扮演中心作用 信号。线粒体健康和功能的维护无疑是至关重要的 - 线粒体 功能障碍有助于与年龄相关的认知能力下降和多种神经退行性疾病。作为 这样的理解神经元完成线粒体质量控制的机制是一个关键目标 为人类健康。 通过一种称为线粒体的过程从神经元中消除了旧的或受损的线粒体，该过程识别 并在神经元内降解它们。我们发现了Young的一个新的且以前未知的功能 成年秀丽隐杆线虫神经元 - 神经元可以选择性地扔掉包含的蜂窝内容物 汇总的人神经退行性疾病蛋白和/或氧化的线粒体。值得注意的是，类似 最近在小鼠大脑中报道了线粒体远程降解的现象，这表明 线粒体质量控制的保守组成部分。 我们已经观察到线粒体功能的遗传障碍可以增加挤压数量 事件，表明可能会特别抛出线粒体功能失调。我们建议 神经元素挤出现象构成了一个重要但未知的途径 神经元通过摆脱功能失调的线粒体来维护其功能 - 弄脏垃圾， 而不是在现场降解它。 我们将使用功能强大的秀丽隐杆线虫模型，我们可以轻松地操纵基因并使用荧光 记者在个别神经元中跟踪体内线粒体，以解决有关的两个关键初始问题 线粒体挤出：1）线粒体功能障碍与挤出增加有关 （ROS，裂变/融合，线粒体障碍）？和2）挤出线粒体的神经元是否表现出 比没有的老化更健康？ 呢 我们推测神经元垃圾挤出机制是保守的，并且该途径的功能障碍 可能导致疾病和衰老的神经元下降。便利的基本生物学的机械解剖 实验模型将为与人脑衰老相关的过程提供大量见解 神经退行性疾病，可能会激发新疗法。呢