Research Paper Volume 13, Issue 18 pp 22188—22207
Cx32 inhibits the autophagic effect of Nur77 in SH-SY5Y cells and rat brain with ischemic stroke
- 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
- 2 Department of Good Clinical Practice, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi 214023, China
- 3 Department of Reproductive Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214023, China
- 4 Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
Received: April 16, 2020 Accepted: September 2, 2021 Published: September 22, 2021https://doi.org/10.18632/aging.203526
How to Cite
Copyright: © 2021 Ping et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The pathogenesis of cerebral ischemia-reperfusion (I/R) is complex. Cx32 expression has been reported to be up-regulated in ischemic lesions of aged human brain. Nevertheless, the function of Cx32 during cerebral I/R is poorly understood. Autophagy is of vital importance in the pathogenesis of cerebral I/R. In the current study, we found that oxygen-glucose deprivation/reoxygenation (OGD/R) or I/R insult significantly induced the up-regulation of Cx32 and activation of autophagy. Inhibition of Cx32 alleviated OGD/R or I/R injury, and further activated autophagy. In addition, Nur77 expression was found to be up-regulated after OGD/R or I/R. After inhibiting Cx32, the expression of Nur77 was further increased and Nur77 was translocated from nucleus to mitochondrial. Inhibition of Cx32 also activated mitophagy by promoting autophagosome formation and up-regulating the expression of mitochondrial autophagy marker molecules. Of note, in the siNur77-transfected cells, the number of dysfunctional mitochondrial was increased, and mitophagy was suppressed, which aggravated OGD/R-induced neuronal injury. In conclusion, Cx32 might act as a regulatory factor of Nur77 controlling neuronal autophagy in the brains. Understanding the mechanism of this regulatory pathway will provide new insight into the role Cx32 and Nur77 in cerebral ischemia, offering new opportunities for therapeutics.
3-MA: 3-methyladenine; Bcl-2: B-cell CLL/lymphoma 2; BNIP3: BCL2/adenovirus E1B 19-kDa protein-interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B 19-kDa protein-interacting protein 3-like; GFP: green fluorescent protein; JC-1: 5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide; LAMP1/2: lysosomal-associated membrane protein ½; LC3-I/II: light chain 3I/II; mTOR: mammalian target of rapamycin; Ctrl: control; OGD/R: oxygen-glucose deprivation/reoxygenation; I/R: ischemia/reperfusion; ROS: reactive oxygen species; siRNA: small interfering RNA; Cx: Connexins; MCAO: middle cerebral artery occlusion; MDA: Malondialdehyde; Co-IP: Coimmunoprecipitation; GABARAP: gama-aminobutyric acid receptor-associated protein.