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 H(2)O(2)-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.