The mitochondrial fission-mitophagy axis drives neuronal S-phase arrest and hippocampal damage in co-exposure to polystyrene nanoplastics and lead

Smaller polystyrene nanoplastics (PS-NPs) can act as vectors for co-existing environmental heavy metals like lead (Pb). The complex neurological health risks posed by these co-exposures are concerning, but their combined neurotoxicity mechanism remains unclear. This study investigated the individual and combined toxic impacts of PS-NPs (5 mg/kg in mice, 50 μg/mL in HT22 cells) and Pb (100 mg/L in mice, 10 μg/mL in HT22 cells) on hippocampal neurons, and explored the underlying mechanisms. The results show that PS-NPs facilitate Pb accumulation in the mouse hippocampus and HT22 cells via clathrin-mediated endocytosis. Co-exposure to Pb and PS-NPs, but not either alone, synergistically induced hippocampal neuronal damage, manifesting as synaptic loss and memory deficits in mice, and triggered S-phase cell cycle arrest alongside oxidative stress in HT22 cells. Mechanistically, Pb+PS-NPs caused mitochondrial dysfunction and shifted mitochondrial dynamics towards excessive fission, evidenced by upregulated DRP1/p-DRP1^Ser616 and downregulated MFN1/2, and activated PINK1/Parkin-mediated Mitophagy. Crucially, inhibition of this mitochondrial fission-mitophagy axis by Mitochondrial Division Inhibitor 1 or cyclosporin A attenuated mitochondrial damage, rescued S-phase arrest, and alleviated hippocampal neuronal injury. Our findings unveil a novel pathway wherein the mitochondrial fission-mitophagy axis drives neuronal cell cycle arrest and cognitive impairment, providing new insights into the risks of combined pollutant exposure.