Roles of glutathione peroxidase 4 on the mercury-triggered ferroptosis in renal cells: Implications for the antagonism between selenium and mercury

Understanding of how mercury species cause cellular impairments at the molecular level is critical for explaining the detrimental effects of mercury exposure on the human body. Previous studies have reported that inorganic and organic mercury compounds can induce Apoptosis and necrosis in a variety of cell types, but more recent advances reveal that mercuric mercury (Hg2+) and methylmercury (CH3Hg+) may result in Ferroptosis, a distinct form of programmed cell death. However, it is still unclear which protein targets are responsible for Ferroptosis induced by HgCl2 and CH3HgCl. In this study, human embryonic kidney 293T (HEK293T) cells were used to investigate how HgCl2 and CH3HgCl trigger Ferroptosis, given their nephrotoxicity. Our results demonstrate that Glutathione Peroxidase 4 (GPx4) plays a key role in lipid peroxidation and Ferroptosis in renal cells induced by HgCl2 and CH3HgCl. The expression of GPx4, the only lipid repair Enzyme in mammal cells, was downregulated in response to Hg2+ and CH3Hg+ stress. More importantly, the activity of GPx4 could be markedly inhibited by CH3HgCl, owing to the direct binding of the selenol group (-SeH) in GPx4 to CH3Hg+. Selenite supplementation was demonstrated to enhance the expression and activity of GPx4 in renal cells, and consequently relieve the cytotoxicity of CH3HgCl, suggesting that GPx4 is a crucial modulator implicated in the Hg-Se antagonism. These findings highlight the importance of GPx4 in Hg-induced Ferroptosis, and provide an alternative explanation for how Hg2+ and CH3Hg+ induce cell death.

antagonism; ferroptosis; glutathione peroxidase 4; mercury; nephrotoxicity; selenium.