Conclusions
FTO overexpression suppressed FYN expression through m6A modification, thereby subduing Drp1 activity and relieving cerebral I/R injury.
Methods
The cerebral I/R models were established in mice via the temporary middle cerebral artery occlusion/reperfusion (tMCAO/R) and hypoxia/reoxygenation models were induced in mouse hippocampal neurons via oxygen-glucose deprivation/reoxygenation (OGD/R). After the gain- and loss-of-function assays, related gene expression was detected, along with the examination of mitochondrial fission, OS- and ferroptosis-related marker levels, neuronal degeneration and cerebral infarction, and cell viability and apoptosis. The binding of FTO to FYN, m6A modification levels of FYN, and the interaction between FYN and Drp1 were evaluated.
Results
FTO was downregulated and FYN was upregulated in tMCAO/R mouse models and OGD/R cell models. FTO overexpression inhibited mitochondrial fission, OS, and ferroptosis to suppress cerebral I/R injury in mice, which was reversed by further overexpressing FYN. FTO overexpression also suppressed mitochondrial fission and ferroptosis to increase cell survival and inhibit cell apoptosis in OGD/R cell models, which was aggravated by additionally inhibiting DRP1. FTO overexpression inhibited FYN expression via the m6A modification to inactive Drp1 signaling, thus reducing mitochondrial fission and ferroptosis and enhancing cell viability in cells. Conclusions: FTO overexpression suppressed FYN expression through m6A modification, thereby subduing Drp1 activity and relieving cerebral I/R injury.