Dissecting mechanisms of mitochondiral extrusion from C. elegans neurons

线粒体在神经元能量产生、代谢、钙平衡和ROS中发挥中心作用 发信号。维持线粒体的健康和功能是毋庸置疑的关键--线粒体 功能障碍会导致与年龄相关的认知能力下降和多种神经退行性疾病。AS 因此，了解神经元完成线粒体质量控制的机制是一个关键目标 为了人类健康。 陈旧或受损的线粒体通过一种名为有丝分裂的过程从神经元中消除，这种过程识别 并在神经元内降解它们。我们发现了一个以前不为人知的新特征 成年线虫神经元--神经元可以选择性地丢弃细胞内容物包，包括 聚集的人类神经退行性疾病蛋白和/或氧化的线粒体。值得注意的是，类似的 最近在小鼠大脑中报告了线粒体远程降解的现象，这表明 线粒体挤出可能是线粒体质量控制的保守成分。 我们观察到线粒体功能的遗传损伤可以增加挤出的数量 事件，这表明功能失调的线粒体可能被明确地抛出。我们建议， 神经元挤出现象构成了一条重要但目前尚不清楚的途径，通过这种途径 神经元通过清除功能失调的线粒体来维持其功能--丢弃垃圾， 而不是在现场将其降级。 我们将使用强大的线虫模型，在该模型中，我们可以轻松地操纵基因和使用荧光 记者追踪单个神经元体内的线粒体，以解决两个关键的初始问题 线粒体挤出：1)哪些类型的线粒体功能障碍与挤出增加有关 (ROS，分裂/融合，吞丝障碍)？，以及2)挤出线粒体的神经元是否表现出以下特征 比那些不健康的人更健康的衰老吗？ 好了！ 我们推测神经元垃圾排出机制是保守的，而这一通路的功能障碍 可能会导致神经元在疾病和衰老中的衰退。基础生物学的机械剖析 实验模型将提供相当大的洞察与人类大脑老化和 神经退行性疾病，可能会启发新的治疗方法。好了！

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. !