Mitophagy, the selective removal of damaged mitochondria, is thought to be critical to maintain neuronal homeostasis. Mutations of proteins in the pathway cause neurodegenerative diseases, suggesting defective mitochondrial turnover contributes to neurodegeneration. In primary rat hippocampal neurons, we developed a mitophagy induction paradigm where mild oxidative stress induced low levels of mitochondrial damage. Mitophagy-associated proteins were sequentially recruited to depolarized mitochondria followed by sequestration into autophagosomes. The localization of these mitophagy events had a robust somal bias. In basal and induced conditions, engulfed mitochondria remained in non-acidified organelles for hours to days, illustrating efficient autophagosome sequestration but delayed lysosomal fusion or acidification. Furthermore, expression of an ALS-linked mutation in the pathway disrupted mitochondrial network integrity and this effect was exacerbated by oxidative stress. Thus, age-related decline in neuronal health or expression of disease-associated mutations in the pathway may exacerbate the slow kinetics of neuronal mitophagy, leading to neurodegeneration.

中文翻译：

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吞噬的线粒体的降解在神经元介导的线粒体吞噬中是限速的。

线粒体，选择性去除受损的线粒体，被认为对于维持神经元稳态是至关重要的。通路中蛋白质的突变会导致神经退行性疾病，这表明线粒体功能失调会导致神经退行性变。在原代大鼠海马神经元中，我们开发了一种线粒体诱导范例，其中轻度的氧化应激诱导了低水平的线粒体损伤。线粒体相关蛋白被顺序募集到去极化的线粒体中，然后隔离成自噬体。这些线粒体吞噬事件的定位具有强烈的躯体偏差。在基础和诱导条件下，被吞噬的线粒体在非酸化细胞器中停留数小时至数天，这说明有效的自噬体螯合但延迟了溶酶体融合或酸化。此外，通路中的ALS关联突变的表达破坏了线粒体网络完整性，氧化应激加剧了这种效应。因此，与年龄相关的神经元健康下降或该途径中疾病相关突变的表达可能加剧神经元线粒体吞噬的缓慢动力学，从而导致神经变性。