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Molecular Neurobiology

, Volume 55, Issue 8, pp 6369–6386 | Cite as

Inhibition of Peroxynitrite-Induced Mitophagy Activation Attenuates Cerebral Ischemia-Reperfusion Injury

  • Jinghan Feng
  • Xingmiao Chen
  • Binghe Guan
  • Caiming Li
  • Jinhua Qiu
  • Jiangang Shen
Article

Abstract

Activated autophagy/mitophagy has been intensively observed in ischemic brain, but its roles remain controversial. Peroxynitrite (ONOO), as a representative of reactive nitrogen species, is considered as a critical neurotoxic factor in mediating cerebral ischemia-reperfusion (I/R) injury, but its roles in autophagy/mitophagy activation remain unclear. Herein, we hypothesized that ONOO could induce PINK1/Parkin-mediated mitophagy activation via triggering dynamin-related protein 1 (Drp1) recruitment to damaged mitochondria, contributing to cerebral I/R injury. Firstly, we found PINK1/Parkin-mediated mitophagy activation was predominant among general autophagy, leading to rat brain injury at the reperfusion phase after cerebral ischemia. Subsequently, increased nitrotyrosine was found in the plasma of ischemic stroke patients and ischemia-reperfused rat brains, indicating the generation of ONOO in ischemic stroke. Moreover, in vivo animal experiments illustrated that ONOO was dramatically increased, accompanied with mitochondrial recruitment of Drp1, PINK1/Parkin-mediated mitophagy activation, and progressive infarct size in rat ischemic brains at the reperfusion phase. FeTMPyP, a peroxynitrite decomposition catalyst, remarkably reversed mitochondrial recruitment of Drp1, mitophagy activation, and brain injury. Intriguingly, further study revealed that ONOO induced tyrosine nitration of Drp1 peptide, which might contribute to mitochondrial recruitment of Drp1 for mitophagy activation. In vitro cell experiments yielded consistent results with in vivo animal experiments. Taken together, all above findings support the hypothesis that ONOO-induced mitophagy activation aggravates cerebral I/R injury via recruiting Drp1 to damaged mitochondria.

Keywords

Cerebral ischemia-reperfusion injury Autophagy Mitochondria Mitophagy Peroxynitrite Nitrative stress 

Notes

Acknowledgements

We thank the Faculty Core Facility, Li Ka Shing Faculty of Medicine, The University of Hong Kong, for providing the Carl Zeiss LSM 780 used in capturing confocal fluorescent images. We also appreciate the Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, for supplying the MALDI-TOF/TOF tandem mass spectrometry analysis service. Alternatively, we greatly appreciate Lingen Kong, Chunsheng Cai, and Qianwu Zhou in the Department of Neurology and the Clinical Laboratory of Huizhou First People’s Hospital, Huizhou.

Author Contributions

J.-H.F. designed and performed the experiments, analyzed the data, and wrote the manuscript. X.-M.C. and B.-H.G. carried out the clinical trial, detected the ELISA analysis, and analyzed the data. C.-M.L. and J.-H.Q. supervised the clinical trial. J.-G.S conceived of and supervised this research, designed the experiments, and co-wrote the manuscript.

Funding information

This work was supported by the National Natural Science Foundation of China (No. 31570855) and the Research Grants Council, University Grants Committee (No. 776512M) and RGC Area of Excellence Sheme (AoE/P-705/16).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2017_859_MOESM1_ESM.doc (6 mb)
ESM 1 (DOC 6162 kb)

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Authors and Affiliations

  1. 1.School of Chinese Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina
  2. 2.Department of NeurologyHuizhou First People’s HospitalHuizhouChina

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