The mechanism of intracellular metabolism of methylmercury (MeHg) is not fully known. It has been shown that
superoxide (O2(-)), the proximal
reactive oxygen species (ROS) generated by mitochondria, is responsible for MeHg demethylation. Here, we investigated the impact of different mitochondrial respiratory inhibitors, namely
rotenone and
antimycin A, on the O2(-)mediated degradation of MeHg in human
neuroblastoma cells SH-K-SN. We also utilized
paraquat (PQ) which generates O2(-) in the mitochondrial matrix. We found that the cleavage of the
carbon-
metal bond in MeHg was highly dependent on the topology of O2(-) production by mitochondria. Both
rotenone and PQ, which increase O2(-) in the mitochondrial matrix at a dose-dependent manner, enhanced the conversion of MeHg to inorganic
mercury (iHg). Surprisingly,
antimycin A, which prompts emission of O2(-) into the intermembrane space, did not have the same effect even though
antimycin A induced a dose dependent increase in O2(-) emission.
Rotenone and PQ also enhanced the toxicity of sub-toxic doses (0.1 μM) MeHg which correlated with the accumulation of iHg in mitochondria and depletion of
mitochondrial protein thiols. Taken together, our results demonstrate that MeHg degradation is mediated by mitochondrial O2(-), specifically within the matrix of mitochondria when O2(-) is in adequate supply. Our results also show that O2(-) amplifies MeHg toxicity specifically through its conversion to iHg and subsequent interaction with
protein cysteine thiols (R-SH). The implications of our findings in
mercury neurotoxicity are discussed herein.