Releasing Syntaphilin Removes Stressed Mitochondria from Axons Independent of Mitophagy under Pathophysiological Conditions.
Releasing Syntaphilin Removes Stressed Mitochondria from Axons Independent of Mitophagy under Pathophysiological Conditions.
复制标题
DOI：
10.1016/j.neuron.2017.04.004
复制
发表时间：
2017-05-03
期刊：
影响因子：
16.2
通讯作者：
Sheng ZH
中科院分区：
文献类型：
--
作者：
Lin MY;Cheng XT;Tammineni P;Xie Y;Zhou B;Cai Q;Sheng ZH
慢性线粒体应激是与神经退行性疾病相关的核心问题。从轴突上早期去除有缺陷的线粒体是线粒体质量控制的关键步骤。在这里，我们研究了野生型神经元轴突线粒体对轻度应激的反应，以及与萎缩性侧索硬化症（ALS）和阿尔茨海默病（AD）相关的神经元的慢性线粒体缺陷。我们发现，线粒体锚定蛋白syntaphilin通过一种独立于Parkin、Drp1和自噬的线粒体衍生货物的大量释放，触发应激线粒体从轴突上移除。免疫电子显微镜和超分辨率成像显示了突触蛋白货物的出芽，然后它们搭乘晚期核内体向体细胞运输。释放突触蛋白在ALS和ad相关的突变神经元的早期病理阶段也被激活。我们的研究为在激活帕金森介导的线粒体自噬之前，通过snph介导的线粒体应激和运动的协调来维持轴突线粒体质量提供了新的机制见解。Lin和Cheng等人揭示了一种维持轴突线粒体完整性的新机制，即从应激线粒体中释放锚定蛋白syntaphilin，从而在生理和病理条件下促进轴突上功能失调线粒体的清除，然后激活帕金森介导的线粒体自噬。
Chronic mitochondrial stress is a central problem associated with neurodegenerative diseases. Early removal of defective mitochondria from axons constitutes a critical step of mitochondrial quality control. Here we investigate axonal mitochondrial response to mild stress in wild-type neurons and chronic mitochondrial defects in Amytrophic Lateral Sclerosis (ALS)- and Alzheimer’s disease (AD)-linked neurons. We show that stressed mitochondria are removed from axons triggered by the bulk release of mitochondrial anchoring protein syntaphilin via a new class of mitochondria-derived cargos independent of Parkin, Drp1 and autophagy. Immuno-electron microscopy and super-resolution imaging show the budding of syntaphilin cargos, which then share a ride on late endosomes for transport toward the soma. Releasing syntaphilin is also activated in the early pathological stages of ALS- and AD-linked mutant neurons. Our study provides new mechanistic insights into the maintenance of axonal mitochondrial quality through SNPH-mediated coordination of mitochondrial stress and motility before activation of Parkin-mediated mitophagy. Lin and Cheng et al. reveal a new mechanism maintaining axonal mitochondrial integrity by releasing anchoring protein syntaphilin from stressed mitochondria, thus facilitating the removal of dysfunctional mitochondria from axons before activation of Parkin-mediated mitophagy under physiological and pathological conditions.