Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
Reactive sulfur species (e.g., cysteine hydropersulfide; CysSSH, and glutathione hydropersulfide; GSSH) exhibit high nucleophilicity and thus is thought to play an important role in repressing oxidative stress. However, adaptive cell responses to excess reactive sulfur stress are not well understood. Using cystathionine gamma-lyase as a CysSSH-producing enzyme overexpression to induce sulfur stress, we showed in vivo and in vitro that levels of CysSSH are strictly regulated in mice via CysSSH export from tissues and cells, suggesting an adaptive response to reactive persulfides. Interestingly, among all amino acids, cystine (CysSSCys) was found to be essential for CysSSH export from primary mouse hepatocytes, HepG2 cells, and HEK293 cells during excess reactive sulfur stress, that the cystine/glutamate transporter (SLC7A11) contributes, at least partially, to CysSSH export. We established HepG2 cell lines with knockout of SLC7A11 and used them to confirm SLC7A11 as the predominant antiporter of CysSSCys and CysSSH. We observed that the poor efflux of excess CysSSH from the cell enhanced cellular stresses induced by excess reactive sulfur exposure, such as polysulfidation of intracellular proteins, mitochondrial damage, and cytotoxicity.
These results suggest that a cellular mechanism for maintaining intracellular reactive sulfur homeostasis via extracellular efflux of excess reactive sulfur could prevent the adverse effects of excess reactive sulfur. Our findings suggested the existence of a safeguard against excess reactive sulfur.
