Sevoflurane activates ATF4/NSUN7/PRKCD axis to induce neurotoxicity and cognitive impairment by promoting neuron mitochondrial fission.

Sevoflurane (SEV) had been confirmed to induce mitochondrial dysfunction to accelerate neurotoxicity. NOL1/NOP2/Sun domain family member 7 (NSUN7) is involved in the regulation of the progression of neurological dysfunction. The present study aims to explore whether SEV mediates mitochondrial dynamics to exert neurotoxicity by regulating NSUN7-related pathway. Normal mice and NSUN7 knockout (KO) mice were exposed to SEV (obtained from Baxter Healthcare Corporation). Cognitive function of mice was assessed by morris water maze test. HE and Nissl staining, inflammatory factors and ROS levels were used to evaluate neuron injury. Western blot, qRT-PCR or immunofluorescence staining were used to detect the expression of NSUN7, mitochondrial fusion/fission-related markers, protein kinase C delta (PRKCD) and activating transcription factor 4 (ATF4). Neurons isolated from mice hippocampal tissues were treated with SEV, and cell viability and apoptosis were determined using CCK8 assay and flow cytometry. The regulation of NSUN7 on PRKCD, as well as ATF4 on NSUN7, was evaluated using dot blot, RIP, dual-luciferase reporter or ChIP assay. SEV stimulation could enhance mitochondrial fission and NSUN7 expression in hippocampal neurons of mice. NSUN7 knockdown repressed mitochondrial fission to relieve SEV-induced neuron injury, and NSUN7-KO ameliorated SEV-induced neurocognitive dysfunction in mice. Besides, NSUN7 facilitated the PRKCD stability and translation by 5-methylcytosine modification, and the suppressive effect of NSUN7 knockdown on SEV-induced neuron injury could be reversed by PRKCD overexpression. Also, ATF4 activated the transcription of NSUN7, and its knockdown alleviated SEV-induced neuron injury by inhibiting mitochondrial fission through downregulating NSUN7. Meanwhile, SEV aggravated neurotoxicity and cognitive impairment in mice by activating the ATF4/NSUN7/PRKCD axis. Collectively, SEV-induced neurotoxicity is associated with mitochondrial fission and ATF4/NSUN7/PRKCD pathway activation, providing new ideas for alleviating SEV-induced neurotoxicity.