Methylmercury (MeHg), an environmental toxin, may specifically cause neurological disorders. Recent studies have reported that autophagy can be induced by metals and be involved in metal cytotoxicity. However, the role of autophagy in MeHg-induced neurotoxicity remains unknown. Here, we demonstrate that MeHg induces mTOR-independent autophagy through JNK/Vps34 complex pathway, which further promotes autophagosome accumulation and neuronal cell death. In addition to cell death, MeHg increased LC3-II expression in a concentration- and time-dependent manner in neuronal cells; furthermore, western blot analysis of LC3-II expression under baf A1-treated condition indicates that MeHg activates autophagy induction. However, we found lysosomal degradative function was impaired by MeHg. Under this condition, MeHg-activated autophagy induction would elicit autophagosome accumulation and cell death. Consistent with this inference, the autophagy inhibitor decreased the MeHg-induced autophagosome accumulation and neuronal cells death, whereas the autophagy inducers further augmented MeHg cytotoxicity. Then, the mechanism of autophagy induction is investigated. We show that MeHg-induced autophagy is mTOR-independent. Vacuolar protein sorting 34 (Vps34) complex is critical for mTOR-independent autophagy. MeHg induced the interaction between Beclin1 and Vps34 to form Vps34 complex. Importantly, knockdown of Vps34 inhibited autophagy induction by MeHg. Furthermore, we found that JNK, but not p38 or ERK, promoted the formation of Vps34 complex and autophagy induction. Finally, inhibition of JNK or downregulation of Vps34 decreased autophagosome accumulation and alleviated MeHg-induced neuronal cell death. The present study implies that inhibiting JNK/Vps34 complex autophagy induction pathway may be a novel therapeutic approach for the treatment of MeHg-induced neurotoxicity.

Cadmium (Cd), an environmental toxin, may cause neurological disorders. We studied the role and activation mechanism of FoxO3a in Cd-induced oxidative stress. In addition to oxidative stress, Cd activated the antioxidant defense system in neuronal cells. Furthermore, by using Western blot and confocal microscopy, we found that Cd induced nuclear expression of FoxO3a. Importantly, knockdown of FoxO3a significantly suppressed its target SOD2 protein expression and elevated the level of intracellular ROS, ultimately reducing cell viability in Cd-exposed neuronal cells. These results suggest the protective effect of FoxO3a is associated with oxidative stress resistance. Then, we investigated the activation mechanism of FoxO3a. Our results indicate that the nuclear expression of FoxO3a by Cd may be independent of Akt, which is generally regarded as an important negative regulator of FoxO3a. Furthermore, we found that p38 regulated the nuclear expression of FoxO3a in Cd-exposed cells. Finally, we demonstrate that the p38-FoxO3a pathway inhibits Cd-induced oxidative stress. These signaling molecules may be used as a novel biological marker of Cd-induced oxidative stress and provide potential therapeutic approaches for it.