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

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.

Automated summary

The study found that ZFP36 protects against neuronal injury induced by OGD/R by inhibiting NOX4-mediated DRP1 activation and excessive mitochondrial fission. Targeting ZFP36 pharmacologically may provide new therapeutic strategies for treating cerebral I/R injury.