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.

受损的线粒体在称为线粒体自噬的过程中被选择性地从细胞中去除。这种线粒体质量控制机制对于神经元稳态非常重要，通路成分的突变是帕金森病和肌萎缩侧索硬化症 (ALS) 的病因。在这里，我们讨论我们最近的工作，使用一种新颖的温和诱导范式来研究原代神经元线粒体自噬的时空动力学。使用活细胞成像，我们发现线粒体自噬相关蛋白易位到去极化的线粒体片段。这些线粒体自噬事件主要局限于体细胞树突区，表明神经元线粒体自噬主要是一种体细胞质量控制机制。受损的线粒体被有效地隔离在自噬体内，但溶酶体融合或酸化显着延迟。令人惊讶的是，被吞噬的线粒体在最初损伤后持续存在于非酸化的囊泡区室中数小时至数天。 ALS 相关突变的表达破坏了线粒体网络的膜电位，而氧化应激加剧了这种效应。重要的是，我们的结果强调了线粒体自噬的缓慢动力学，并表明受损线粒体的缓慢周转可能会增加神经元对神经变性的易感性。