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 μm) 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.