Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 46, Issue 6, Pages 2311-2324Publisher
KARGER
DOI: 10.1159/000489621
Keywords
Autophagy; Cerebral ischemia reperfusion injury; Mitofusin 2; Autophagic flux; Chloroquine
Categories
Funding
- National Natural Science Foundation of China [81430043, 30930093, 81401020]
- National Science and Technology Major Project of China [2013ZX 09J13109-02C]
- National Science and Technology Pillar Program of China [2012BAI11B02]
- Science and Technology Project of Shaanxi [2013KTCQ03-01]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT-14208]
- Key Project of the Twelfth Five-year Plan of Scientific Research of China [AWS11J008]
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Background/Aims: Autophagy is essential for maintaining cellular homeostasis and the survival of terminally differentiated cells as neurons. In this study, we aim to investigate whether mitofusin 2, a mitochondrial fusion protein, mediates autophagy in cerebral ischemia/reperfusion (I/R) injury. Methods: Primary cultured neurons were treated with oxygen-glucose deprivation/reperfusion to mimic cerebral I/R injury in vitro. Autophagosomes were visualized upon TEM. Autophagy-markers were then detected to monitor autophagy by western-blot and real-time PCR, and the autophagic flux was tracked with a mRFP-GFP-LC3 construct by fluorescence as well as autophagy inhibitors and agonists. The up-and downregulation of Mfn2 were through transfecting a lentivirusexpression vector respectively. And neuronal injury was detected by cell counting kit and TUNEL assay. Results: Results showed I/R increased autophagosome formation and inhibited autolysosome degradation. Furthermore, use of autophagy related agents demonstrated that I/R injury was caused by insufficient autophagy and aggravated by impaired autophagic degradation. The results also indicated that mitofusin 2 could ameliorate I/R injury through increasing autophagosome formation and promoting the fusion of autophagosomes and lysosomes. In contrast, downregulation of mitofusin 2 aggravated the I/R injury by inhibiting autophagosome formation and the fusion of autophagosomes and lysosomes. Additionly, mitofusin 2 overexpression did not lead to autolysosome accumulation induced by I/R. Conclusions: In summary, this study explicitly demonstrated that mitofusin 2 could ameliorate I/R injury mainly through promoting autophagy, which represented a potential novel strategy for neuroprotection against cerebral I/R damage. (C) 2018 The Author(s) Published by S. Karger AG, Basel
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