Hydrogen gas protects IP3Rs by reducing disulfide bridges in human keratinocytes under oxidative stress

Based on the oxidative stress theory, aging derives from the accumulation of oxidized proteins induced by reactive oxygen species (ROS) in the cytoplasm. Hydrogen peroxide (H₂O₂) elicits ROS that induces skin aging through oxidation of proteins, forming disulfide bridges with cysteine or methionine sulfhydryl groups. Decreased Ca²⁺ signaling is observed in aged cells, probably secondary to the formation of disulfide bonds among Ca²⁺ signaling-related proteins. Skin aging processes are modeled by treating keratinocytes with H₂O₂. In the present study, H₂O₂ dose-dependently impaired the adenosine triphosphate (ATP)-induced Ca²⁺ response, which was partially protected via co-treatment with β-mercaptoethanol, resulting in reduced disulfide bond formation in inositol 1, 4, 5-trisphosphate receptors (IP₃Rs). Molecular hydrogen (H₂) was found to be more effectively protected H₂O₂-induced IP₃R1 dysfunction by reducing disulfide bonds, rather than quenching ROS. In conclusion, skin aging processes may involve ROS-induced protein dysfunction due to disulfide bond formation, H₂ can protect oxidation of this process.