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

Abstract

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 Hg2+ and CH3Hg+. In this study, human embryonic kidney 293T cells were used to investigate how Hg2+ and CH3Hg+ 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 Hg2+ and CH3Hg+. 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 CH3Hg+, 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 CH3Hg+, suggesting that GPx4 is a crucial modulator implicated in the Hg-Se antagonism. These findings highlight the importance of GPx4 in mercury-induced ferroptosis, and provide an alternative explanation for how Hg2+ and CH3Hg+ induce cell death.

• Authors: Jiahao Chen, Minghao Ma, Ruixia Wang, Ming Gao, Ligang Hu, Sijin Liu, Ming Xu
• Journal: Metallomics : integrated biometal science (Metallomics) Vol. 15 Issue 3 (03 06 2023) ISSN: 1756-591X [Electronic] England
• PMID: 36869799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2023. Published by Oxford University Press.

Chemical References

• Mercury
• Selenium
• Phospholipid Hydroperoxide Glutathione Peroxidase
• Glutathione Peroxidase

Topics

• Animals
• Humans
• Mercury (toxicity, metabolism)
• Selenium (pharmacology)
• Phospholipid Hydroperoxide Glutathione Peroxidase
• Ferroptosis
• Kidney (metabolism)
• Glutathione Peroxidase (metabolism)
• Mammals (metabolism)