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. 2013 Sep;9(9):1321-33.
doi: 10.4161/auto.25132. Epub 2013 Jun 12.

Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance

Xiangnan Zhang  1 , Haijing Yan, Yang Yuan, Jieqiong Gao, Zhe Shen, Yun Cheng, Yao Shen, Rong-Rong Wang, Xiaofen Wang, Wei-Wei Hu, Guanghui Wang, Zhong Chen
Affiliations

Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance

Xiangnan Zhang et al. Autophagy. 2013 Sep.

Erratum in

  • Correction.
    [No authors listed] [No authors listed] Autophagy. 2019 Jun;15(6):1124. doi: 10.1080/15548627.2019.1589725. Epub 2019 Mar 11. Autophagy. 2019. PMID: 30883254 Free PMC article. No abstract available.

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 A 1, 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 and Park2 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.

Keywords: autophagy; cerebral ischemia; mitochondria; mitophagy; neuroprotection.

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