Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Autophagy. 2020 May;16(5):962-964. doi: 10.1080/15548627.2020.1734330. Epub 2020 Mar 4.
Damaged mitochondria are selectively removed from the cell in a process termed mitophagy. This mitochondrial quality control mechanism is important for neuronal homeostasis, and mutations in pathway components are causative for Parkinson disease and amyotrophic lateral sclerosis (ALS). Here, we discuss our recent work using a novel mild induction paradigm to investigate the spatiotemporal dynamics of mitophagy in primary neurons. Using live-cell imaging, we find that mitophagy-associated proteins translocate to depolarized mitochondrial fragments. These mitophagic events were primarily localized to somatodendritic compartments, suggesting neuronal mitophagy is primarily a somal quality control mechanism. Damaged mitochondria were efficiently sequestered within autophagosomes, but lysosomal fusion or acidification was significantly delayed. Surprisingly, engulfed mitochondria persisted in non-acidified vesicular compartments for hours to days after initial damage. Expression of an ALS-associated mutation disrupted the membrane potential of the mitochondrial network, and oxidative stress exacerbated this effect. Importantly, our results highlight the slow kinetics of mitophagy and suggest that slow turnover of damaged mitochondria may increase neuronal susceptibility to neurodegeneration.
受损的线粒体在一种称为自噬的过程中被选择性地从细胞中清除。这种线粒体质量控制机制对神经元稳态很重要，并且途径成分的突变是帕金森病和肌萎缩侧索硬化症 (ALS) 的原因。在这里，我们讨论了我们最近使用一种新的温和诱导范例来研究原代神经元中自噬的时空动力学的工作。使用活细胞成像，我们发现与自噬相关的蛋白质向去极化的线粒体片段转移。这些自噬事件主要定位于体树突区室，表明神经元自噬主要是一种体质量控制机制。受损的线粒体被有效地隔离在自噬体中，但溶酶体融合或酸化明显延迟。令人惊讶的是，吞噬的线粒体在初始损伤后数小时到数天内仍存在于未酸化的囊泡区室中。ALS 相关突变的表达破坏了线粒体网络的膜电位，氧化应激加剧了这种效应。重要的是，我们的结果强调了自噬的缓慢动力学，并表明受损线粒体的缓慢周转可能会增加神经元对神经退行性变的易感性。
