1. Academic Validation
  2. ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway

ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway

  • Brain Res Bull. 2022 Feb;179:57-67. doi: 10.1016/j.brainresbull.2021.12.003.
Hengjiang Guo 1 Yan Jiang 1 Zhiqing Gu 1 Lulu Ren 1 Change Zhu 1 Shenghua Yu 1 Rong Wei 2
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200062, China.
  • 2 Department of Anesthesiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200062, China. Electronic address: [email protected].
Abstract

The imbalance of mitochondrial dynamics plays an important role in the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Zinc-finger protein 36 (ZFP36) has been documented to have neuroprotective effects, however, whether ZFP36 is involved in the regulation of neuronal survival during cerebral I/R injury remains unknown. In this study, we found that the transcriptional and translational levels of ZFP36 were increased in immortalized hippocampal HT22 neuronal cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ZFP36 gene silencing exacerbated OGD/R-induced dynamin-related protein 1 (DRP1) activity, mitochondrial fragmentation, oxidative stress and neuronal Apoptosis, whereas ZFP36 overexpression exhibited the opposite effects. Besides, we found that NADPH Oxidase 4 (NOX4) was upregulated by OGD/R, and NOX4 inhibition remarkably attenuated OGD/R-instigated DRP1 activity, mitochondrial fragmentation and neuronal Apoptosis. Further study demonstrated that ZFP36 targeted NOX4 mRNA directly by binding to the AU-rich elements (AREs) in the NOX4 3'-untranslated regions (3'-UTR) and inhibited NOX4 expression. Taken together, our data indicate that ZFP36 protects against OGD/R-induced neuronal injury by inhibiting NOX4-mediated DRP1 activation and excessive mitochondrial fission. Pharmacological targeting of ZFP36 to suppress excessive mitochondrial fission may provide new therapeutic strategies in the treatment of cerebral I/R injury.

Keywords

DRP1; Mitochondrial dysfunction; Mitochondrial fission; Neuronal apoptosis; ZFP36.

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