Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, China.
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, China
J Cell Biol. 2019 Jun 3;218(6):1891-1907. doi: 10.1083/jcb.201804101. Epub 2019 Apr 12.
Mitophagy protects against ischemic neuronal injury by eliminating damaged mitochondria, but it is unclear how mitochondria in distal axons are cleared. We find that oxygen and glucose deprivation-reperfusion reduces mitochondrial content in both cell bodies and axons. Axonal mitochondria elimination was not abolished in ;nes- neurons, suggesting the absence of direct mitophagy in axons. Instead, axonal mitochondria were enwrapped by autophagosomes in soma and axon-derived mitochondria prioritized for elimination by autophagy. Intriguingly, axonal mitochondria showed prompt loss of anterograde motility but increased retrograde movement upon reperfusion. Anchoring of axonal mitochondria by syntaphilin blocked neuronal mitophagy and aggravated injury. Conversely, induced binding of mitochondria to dynein reinforced retrograde transport and enhanced mitophagy to prevent mitochondrial dysfunction and attenuate neuronal injury. Therefore, we reveal somatic autophagy of axonal mitochondria in ischemic neurons and establish a direct link of retrograde mitochondrial movement with mitophagy. Our findings may provide a new concept for reducing ischemic neuronal injury by correcting mitochondrial motility.
自噬通过消除受损的线粒体来保护缺血性神经元免受损伤，但尚不清楚远端轴突中的线粒体如何被清除。我们发现，缺氧和葡萄糖剥夺再灌注会降低细胞体和轴突中的线粒体含量。在 nes-神经元中，轴突线粒体的消除并没有被废除，这表明轴突中不存在直接的线粒体自噬。相反，轴突线粒体被自噬体包裹在胞体和轴突中，并且优先通过自噬来消除轴突衍生的线粒体。有趣的是，轴突线粒体在再灌注后迅速失去正向运动，但反向运动增加。突触联蛋白将轴突线粒体锚定，阻断神经元自噬，加重损伤。相反，诱导线粒体与动力蛋白结合增强了逆行运输，并增强了线粒体自噬，以防止线粒体功能障碍和减轻神经元损伤。因此，我们揭示了缺血性神经元中轴突线粒体的胞体自噬，并建立了逆行线粒体运动与线粒体自噬的直接联系。我们的发现可能为通过纠正线粒体运动来减少缺血性神经元损伤提供了一个新概念。
