Unbalanced ER-mitochondrial calcium homeostasis promotes mitochondrial dysfunction and associated apoptotic pathways activation in methylmercury exposed rat cortical neurons

Methylmercury (MeHg) is a cumulative environmental pollutant that can easily cross the blood-brain barrier and cause damage to the brain, mainly targeting the central nervous system. The purpose of this study is to investigate the role of calcium ion (Ca2+) homeostasis between the endoplasmic reticulum (ER) and mitochondria in MeHg-induced neurotoxicity. Rat primary cortical neurons exposed to MeHg (0.25-1 mu m) underwent dose-dependent cell damage, accompanied by increased Ca2+ release from the ER and elevated levels of free Ca2+ in cytoplasm and mitochondria. MeHg also increased the protein and messenger RNA expressions of the inositol 1,4,5-triphosphate receptor, ryanodine receptor 2, and mitochondrial calcium uniporter. Ca2+ channel inhibitors 2-aminoethyl diphenylborinate and procaine reduced the release of Ca2+ from ER, while RR and 4,4 '-diisothiocyanatostilbene-2,2 '-disulfonate inhibited Ca2+ uptake from mitochondria. In addition, pretreatment with Ca2+ chelator BAPTA-AM effectively restored mitochondrial membrane potential levels, inhibited over opening of mitochondrial permeability transition pore, and maintained mitochondrial function stability. Meanwhile, the expression of mitochondrial apoptosis-related proteins recovered to some extent, along with the reduction of the early apoptosis ratio. These results suggest that Ca2+ homeostasis plays an essential role in mitochondrial damage and apoptosis induced by MeHg, which may be one of the important mechanisms of MeHg-induced neurotoxicity.