Kir6.2-KATP channel: A new target for manganese neurotoxicity induced autophagy impairment and oxidative stress injury

Manganese (Mn) is a neurotoxic metal, and epidemiological evidence has demonstrated that chronic occupational exposure to Mn is associated with an elevated risk of neurological disorders. Furthermore, experimental investigations have revealed that autophagy impairment and oxidative stress serve as key contributors to Mn-induced neurotoxicity. Here, we report for the first time the involvement of Kir6.2-KATP channel dysfunction in Mn-induced neurotoxicity. Although previous studies have investigated the relationship between autophagy impairment and Kir6.2, the specific regulatory role of Kir6.2 in autophagy within the context of Mn neurotoxicity has not been reported. We found that Mn exposure inhibits Kir6.2 expression, induces cellular autophagy impairment and oxidative stress, along with ATP depletion. Additionally, we found that exogenous ATP, the antioxidant NAC, and Kir6.2 overexpression can activate autophagy, and reduce reactive oxygen species (ROS) production. These findings suggest a close relationship between autophagy impairment, oxidative stress, Kir6.2 inhibition, and ATP depletion in Mn neurotoxicity. In conclusion, the present study demonstrates for the first time that Mn-induced autophagic dysfunction, which is mediated by the inhibition of Kir6.2 expression, has a potential association with oxidative stress and ATP depletion. These findings elucidate the role of autophagy impairment in Mn neurotoxicity and establish Kir6.2 as a potential therapeutic target for mitigating Mn-induced neurotoxicity.