Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Nitric Oxide. 2019 Oct 1;91:23-34. doi: 10.1016/j.niox.2019.07.004. Epub 2019 Jul 16.
The accumulation of dysfunctional mitochondria induced by the impairment of the autophagy-lysosome pathway (ALP), especially mitophagy is an important cause of cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture (EA) exerts remarkable effects in treating ischemic stroke; however, the detailed mechanism remains unclear. In this study, rats were treated with mitochondrial permeability transition pore (mPTP) opening inhibitor, peroxynitrite (ONOO) scavenger, or selective inhibitor of mitophagy activation during 2-h middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion in combination with EA treatment. RNA-Seq analysis showed that EA treatment in cerebral I/R was linked to the autophagosome, the PI3K/Akt signaling pathway and metabolic pathways. We found that I/R resulted in significantly mitochondrial function impairments including decreased mitochondrial membrane potential (MMP) and ATP levels, aggregation of damaged mitochondria, excessive nitro/oxidative stress, PI3K/Akt/mTOR-mediated ALP dysfunction and deficiency of Pink1/Parkin-mediated mitophagy clearance. The treatment with EA, cyclosporine-A (CsA, a potent inhibitor of mPTP opening) or FeTMPyP (a type of ONOO scavenger) could significantly increase MMP and/or ATP levels, improve mitochondrial function and decrease neuronal injury. At the same time, EA also improved ALP dysfunction and the deficiency of mitophagy clearance; however, mitochondrial division inhibitor-1 (Mdivi-1, a selective inhibitor of mitophagy activation) blocked mitophagy clearance and aggravated neuronal injury. Taken together, EA ameliorates nitro/oxidative stress-induced mitochondrial functional damage and decreases the accumulation of damaged mitochondria via Pink1/Parkin-mediated mitophagy clearance to protect cells against neuronal injury in cerebral I/R.
功能失调的线粒体的积累是由自噬-溶酶体途径（ALP）的损伤引起的，尤其是线粒体自噬，这是脑缺血再灌注（I / R）损伤的一个重要原因。电针（EA）在治疗缺血性中风方面具有显著的效果；然而，其详细的机制尚不清楚。在这项研究中，在 2 小时大脑中动脉闭塞（MCAO）后 24 小时再灌注期间，用线粒体通透性转换孔（mPTP）开放抑制剂、过氧亚硝酸盐（ONOO）清除剂或选择性的线粒体自噬激活抑制剂与 EA 治疗相结合，对大鼠进行处理。RNA-Seq 分析表明，EA 治疗脑 I / R 与自噬体、PI3K / Akt 信号通路和代谢途径有关。我们发现，I / R 导致线粒体功能显著受损，包括线粒体膜电位（MMP）和 ATP 水平降低、受损线粒体聚集、过氮/氧化应激、PI3K / Akt / mTOR 介导的 ALP 功能障碍以及 Pink1 / Parkin 介导的线粒体自噬清除不足。EA、环孢菌素 A（CsA，mPTP 开放的有效抑制剂）或 FeTMPyP（一种 ONOO 清除剂）的治疗可以显著增加 MMP 和/或 ATP 水平，改善线粒体功能并减少神经元损伤。同时，EA 还改善了 ALP 功能障碍和线粒体自噬清除不足；然而，线粒体分裂抑制剂-1（Mdivi-1，线粒体自噬激活的选择性抑制剂）阻断了线粒体自噬清除并加重了神经元损伤。总之，EA 通过 Pink1 / Parkin 介导的线粒体自噬清除来改善氮/氧化应激诱导的线粒体功能损伤并减少受损线粒体的积累，从而保护细胞免受脑 I / R 中的神经元损伤。
