MK-3903

Arsenic contamination of groundwater remains a serious public health problem worldwide. Arsenic-induced neurotoxicity receives increasing attention, however, the mechanism remains unclear. Hippocampal neuronal death is regarded as the main event of arsenic-induced cognitive dysfunction. Mitochondria lesion is closely related to cell death, however, the effects of arsenic on PGAM5-regulated mitochondrial dynamics has not been documented. Crosstalk between autophagy and apoptosis is complicated and autophagy has a dual role in the apoptosis pathways in neuronal cells. In this study, arsenic exposure resulted in mitochondrial PGAM5 activation and subsequent activation of apoptosis and AMPK-mTOR dependent autophagy. Intervention by autophagy activator Rapamycin or inhibitor 3-MA, both targeting at mTOR, accordingly induced activation or inhibition of apoptosis. Intervention by MK-3903 or dorsomorphin, activator or inhibitor of AMPK, received similar results. Our findings suggested that arsenic-induced PGAM5 activation played a role in AMPK-mTOR dependent autophagy and arsenic induced autophagy-dependent apoptosis in hippocampal neurons via AMPK/mTOR signaling pathway.