Voltage-dependent anion channels (VDACs) promote mitophagy to protect neuron from death in an early brain injury following a subarachnoid hemorrhage in rats
Voltage-dependent anion channels (VDACs) promote mitophagy to protect neuron from death in an early brain injury following a subarachnoid hemorrhage in rats
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DOI：
10.1016/j.brainres.2014.05.021
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发表时间：
2014-07-21
期刊：
影响因子：
2.9
通讯作者：
Zhou, Changman
中科院分区：
文献类型：
--
作者：
Li, Jian;Lu, Jianfei;Zhou, Changman
线粒体自噬（mitophagy）一词是用来描述通过自噬选择性去除线粒体的，但这个过程本身仍然存在争议，特别是在蛛网膜下腔出血（SAH）后的早期。在本研究中，我们研究了大鼠SAH损伤后48小时线粒体自噬的作用。为了专门评估线粒体自噬是否可以通过电压依赖性阴离子通道（VDAC）与微管相关蛋白1轻链3相互作用来诱导神经元中的细胞凋亡和坏死，我们使用了VDAC 1 siRNA和激活剂雷帕霉素（PAPA）。112只雄性SD大鼠随机分为4组：假手术组、SAH组、SAH+ VDAC 1 siRNA组和SAH+RAPA组。测量的结果包括死亡率、脑水肿、BBB破坏和神经行为测试。我们还使用蛋白质印迹技术来分析关键的线粒体吞噬/自噬蛋白和促凋亡蛋白如ROS、VDAC 1、LC-3 II和Caspase-3的表达。雷帕霉素治疗显著改善了死亡率、脑水肿和神经行为缺陷; SAM损伤后，雷帕霉素减少了神经元中的凋亡和坏死细胞死亡。然而，VDAC 1 siRNA加重了SAH后的脑损伤。免疫组织化学染色和蛋白质印迹分析表明，VDAC 1 siRNA给药后，VDAC 1，LC 3 II的表达下降，ROS和Caspase-3的表达增加。总之，SAH损伤后VDAC 1诱导的线粒体自噬实际上可能在神经保护中发挥重要作用，其机制可能是通过减弱凋亡和坏死分子途径。这意味着功能完整性的保留和死亡率的改善。(C)2014爱思唯尔有限公司版权所有。
The term mitophagy is coined to describe the selective removal of mitochondria by autophagy but the process itself is still contentious, especially in the early period following subarachnoid hemorrhage (SAH). In the present study, we investigated the role of mitophagy following 48 h after SAH injury in rats. Specifically evaluating whether mitophagy, through voltage dependant anion channels (VDACs) interacting with microtubule-associated protein 1 light chain 3, could orchestrate the induction of apoptotic and necrotic cell death in neurons, a VDAC1siRNA and an activitor Rapamycian (PAPA), were engaged. One hundred and twelve male Sprague-Dawley rats were randomly divided into 4 groups: Sham, SAH, SAH+VDAC1siRNA, and SAH+RAPA. Outcomes measured included mortality rate, brain edema, BBB disruption, and neurobehavioral testing. We also used western blotting techniques to analyze the expressions of key mitophagic/autophagic proteins and pro-apoptotic protein such as ROS, VDAC1, LC-3II and Caspase-3. Rapamycin treatment significantly improved the mortality rate, cerebral edema, and neurobehavioral deficits; apoptotic and necrotic cell death in neurons were reduced by Rapamycin following SAM injury. However, VDAC1siRNA worsened the brain injury following SAH. Immunohistochemical staining and western blot analysis demonstrated a decreased expression of VDAC1, LC3II, and an increase of ROS and Caspase-3 followed by VDAC1siRNA administration. In conclusion, mitophagy induced by VDAC1 following SAH injury may in fact play a significant role in neuroprotection, the mechanism which may be through the attenuation of the apoptosic and necrosic molecular pathways. This translates a preservation of functional integrity and an improvement in mortality. (C) 2014 Elsevier B.V. All rights reserved.