CDK5/Drp1-mediated Mitochondrial Dysfunction Drives 1-Bromopropane-induced Hippocampal Neurotoxicity in Mice

Occupational exposure to 1-bromopropane (1-BP) has been linked to impairments in learning and memory; however, the molecular mechanisms underlying these effects remain incompletely defined. Cyclin-dependent kinase 5 (CDK5), a critical regulator of neuronal function and synaptic plasticity, is aberrantly activated in multiple neurodegenerative conditions and toxin-induced neuronal injury. Here, we investigated whether CDK5 contributes to 1-BP-induced hippocampal neurotoxicity by promoting mitochondrial dysfunction. Using mouse and N2a cell models, we showed that 1-BP exposure triggered calpain-mediated proteolysis, increased p25 generation, and enhanced CDK5 activation in hippocampal neurons and N2a cells. CDK5 activation was accompanied by elevated Drp1 expression and phosphorylation, indicative of excessive mitochondrial fission and fragmentation. These mitochondrial abnormalities were associated with neuronal death, as evidenced by increased TUNEL-positive cells and upregulation of the necroptosis-related proteins RIPK1 and MLKL. Pharmacological inhibition of CDK5 with roscovitine markedly suppressed 1-BP-induced mitochondrial fission and neuronal necroptosisin N2a cells. Consistently, heterozygous Cdk5 haploinsufficiency mitigated mitochondrial structural and functional damage, reduced hippocampal neuronal loss, and improved learning and memory deficits in 1-BP-exposed mice. Together, these findings identify the CDK5/Drp1 axis as a critical mediator of 1-BP-induced mitochondrial dysfunction and hippocampal neuronal injury, providing mechanistic insight into the neurotoxicity of 1-BP.