Molecular hydrogen protects against oxidative stress-induced SH-SY5Y neuroblastoma cell death through the process of mitohormesis

Inhalation of molecular hydrogen (H-2) gas ameliorates oxidative stress-induced acute injuries in the brain. Consumption of water nearly saturated with H-2 also prevents chronic neurodegenerative diseases including Parkinson's disease in animal and clinical studies. However, the molecular mechanisms underlying the remarkable effect of a small amount of H-2 remain unclear. Here, we investigated the effect of H-2 on mitochondria in cultured human neuroblastoma SH-SY5Y cells. H-2 increased the mitochondrial membrane potential and the cellular ATP level, which were accompanied by a decrease in the reduced glutathione level and an increase in the superoxide level. Pretreatment with H-2 suppressed H2O2-induced cell death, whereas post-treatment did not. Increases in the expression of anti-oxidative enzymes underlying the Nrf2 pathway in H-2-treated cells indicated that mild stress caused by H-2 induced increased resistance to exacerbated oxidative stress. We propose that H-2 functions both as a radical scavenger and a mitohormetic effector against oxidative stress in cells.