Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: The role of inhibition of Drp1 in ischemic brain damage
Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: The role of inhibition of Drp1 in ischemic brain damage
复制标题
缺氧/缺血应激后线粒体自噬以 Drp1 依赖性方式诱导：抑制 Drp1 在缺血性脑损伤中的作用
DOI：
10.1016/j.neuropharm.2014.07.002
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发表时间：
2014-11-01
影响因子：
4.7
通讯作者：
Chen, Nai-Hong
中科院分区：
文献类型：
--
作者：
Zuo, Wei;Zhang, Shuai;Chen, Nai-Hong
线粒体功能障碍涉及多种疾病，包括代谢和神经退行性疾病。线粒体动力学与线粒体自噬（mitochondrial autophagy）的关系引起了越来越多的关注，线粒体自噬是维持线粒体稳态的功能失调的线粒体降解的关键。然而，急性缺血性损伤中线粒体分裂及其在损伤线粒体清除中的作用尚未阐明。在这里，我们表明，缺氧/缺血条件下导致的线粒体碎片和诱导线粒体自噬在永久性大脑中动脉闭塞（pMCAO）大鼠和氧-葡萄糖剥夺（OGD）PC 12细胞。通过药物抑制剂或siRNA抑制Drp 1主要通过选择性阻断线粒体自噬而不影响线粒体生物合成和非选择性自噬导致受损线粒体的积累。在pMCAO大鼠模型中，Drp 1抑制剂增加了梗死体积并加重了神经功能缺损。我们证明了通过抑制Drp 1而破坏线粒体分裂的破坏性作用有助于受损的线粒体介导的损伤，如ROS产生、cyt-c释放和caspase-3的激活。综上所述，我们证明了在缺氧/缺血应激下，在缺氧/缺血损伤的早期阶段，Drp 1依赖的线粒体自噬被触发，参与了受损线粒体的清除和细胞的存活。因此，参与选择性去除功能障碍的线粒体的Drp 1相关通路被认为是治疗脑缺血的有效靶点。(C)2014爱思唯尔有限公司版权所有。
Mitochondria dysfunction is implicated in diverse conditions, including metabolic and neurodegenerative disorders. Mitochondrial dynamics has attracted increasing attention as to its relationship with mitochondria autophagy, also known as mitophagy, which is critical for degradation of dysfunctional mitochondria maintaining mitochondrial homeostasis. Mitochondrial fission and its role in clearance of injured mitochondria in acute ischemic injury, however, have not been elucidated yet. Here we showed that hypoxic/ischemic conditions led to fragmentation of mitochondria and induction of mitophagy in permanent middle cerebral artery occlusion (pMCAO) rats and oxygen-glucose deprivation (OGD) PC12 cells. Inhibition of Drp1 by pharmacologic inhibitor or siRNA resulted in accumulation of damaged mitochondria mainly through selectively blocking mitophagy without affecting mitochondrial biogenesis and non-selective autophagy. Drp1 inhibitors increased the infarct volume and aggravated the neurological deficits in a rat model of pMCAO. We demonstrated that the devastating role of disturbed mitochondrial fission by inhibiting Drp1 contributed to the damaged mitochondria-mediated injury such as ROS generation, cyt-c release and activation of caspase-3. Taken together, we proved that under hypoxic/ischemic stress a Drp1-dependent mitophagy was triggered which was involved in the removal of damaged mitochondria and cellular survival at the early stage of hypoxic/ischemic injury. Thus, Drp1 related pathway involved in selective removal of dysfunctional mitochondria is proposed as an efficient target for treatment of cerebral ischemia. (C) 2014 Elsevier Ltd. All rights reserved.