近日，卫生部医学神经生物学重点实验室和浙江省神经生物学重点实验室陈忠教授课题组在国际著名学术期刊Autophagy上发表了题为Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance 的研究论文，该文首次报道了自噬在缺血性脑损伤中的不同作用机制。
Recently, a research group headed by Professor Chen Zhong at Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China and Zhejiang Province Key Laboratory of Neurobiology, College of pharmaceutical sciences, Zhejiang University has published a research paper titled “Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance” in Autophagy, anauthoritative journal in the field of autophagy(IF=12.04). The article reported the mechanisms underlying the effect of autophagy in ischemic injury for the first time.
Ischemic brain injury is one of the leading causes of mortality and disablity, unfortunately, few therapies has been demonstrated effective in the treatment of ischemic stroke. Autophagy is an evolutionarily highly-conserved process, by which intracellular proteins and organelles are degraded in lysosomes to deal with the stressful condition. However, the role of autophagy in ischemic brians was still under debate. Prof. Chen’s group for the first time found that in the reperfusion phase, autophagy protects against ischemic neuronal injury by clearance of damaged mitochondria which otherwise induce apoptosis via PARK2-related mechanisms; in contrast,in the ischemia phase, autophagy aggravated ischemia injury.
The work addressed a longstanding controversial issue in this field, and suggested that mitophagy may be a potential target for cerebral ischemia therapy. Co-first authors of this article are Lecture Dr. Xiangnan Zhang and Ph.D student Haijing Yan. This study was supported by the Key Project of National Natural Science Foundation of China, 973 Projects, China's Post-doctoral Science Fund.
Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance
Xiangnan Zhang, Haijing Yan, Yang Yuan, Jieqiong Gao, Zhe Shen, Yun Cheng, Yao Shen, Rong-Rong Wang, Xiaofen Wang, Wei-Wei Hu, Guanghui Wang, * Zhong Chen
Keywords:autophagy, cerebral ischemia, mitochondria, mitophagy,neuroprotection
Abstract: Cerebral ischemia-reperfusion (I-R) is a complex pathological process. Although autophagy can be evoked by ischemia, its involvement in the reperfusion phase after ischemia and its contribution to the fate of neurons remains largely unknown. In the present investigation, we found that autophagy was activated in the reperfusion phase, as revealed in both mice with middle cerebral artery occlusion and oxygen-glucose deprived cortical neurons in culture. Interestingly, in contrast to that in permanent ischemia, inhibition of autophagy (by 3-methyladenine, bafilomycin A1, Atg7 knockdown or in atg5−/− MEF cells) in the reperfusion phase reinforced, rather than reduced, the brain and cell injury induced by I-R. Inhibition of autophagy either with 3-methyladenine or Atg7 knockdown enhanced the I-R-induced release of cytochrome c and the downstream activation of apoptosis. Moreover, MitoTracker Red-labeled neuronal mitochondria increasingly overlapped with GFP-LC3-labeled autophagosomes during reperfusion, suggesting the presence of mitophagy. The mitochondrial clearance in I-R was reversed by 3-methyladenine and Atg7 silencing, further suggesting that mitophagy underlies the neuroprotection by autophagy. In support, administration of the mitophagy inhibitor mdivi-1 in the reperfusion phase aggravated the ischemia-induced neuronal injury both in vivo and in vitro. PARK2 translocated to mitochondria during reperfusion andPark2 knockdown aggravated ischemia-induced neuronal cell death. In conclusion, the results indicated that autophagy plays different roles in cerebral ischemia and subsequent reperfusion. The protective role of autophagy during reperfusion may be attributable to mitophagy-related mitochondrial clearance and inhibition of downstream apoptosis. PARK2 may be involved in the mitophagy process.