Hydrogen Sulfide Increases Glutathione Production and Suppresses Oxidative Stress in Mitochondria

Hydrogen sulfide (H2S) is a synaptic modulator as well as a neuroprotectant in the brain. We recently showed that H2S protects neurons from oxidative stress by increasing the levels of glutathione (GSH), a major cellular antioxidant, by more than twice that of a control through enhancing the cystine transport. Here we show that H2S enhances the transport of cysteine to increase GSH production more than cystine transport and to redistribute the localization of GSH to mitochondria. The efficiency of GSH production enhanced by H2S is even greater by fourfold under oxidative stress by glutamate. H2S reinstated GSH levels in the fetal brain decreased by ischemia/reperfusion in utero. In addition, Neuro2a cells expressing a mitochondrial H2S-producing enzyme, 3-mercaptopyruvate sulfurtransferase (3MST), along with cysteine aminotransferase (CAT), showed significant resistance to oxidative stress. The present study shows that H2S protects cells from oxidative stress by two mechanisms. It enhances the production of GSH by enhancing cystine/cysteine transporters and redistributes GSH to mitochondria. H2S produced in mitochondria also may directly suppress oxidative stress. It provides a new mechanism of neuroprotection from oxidative stress by H2S. Antioxid. Redox Signal. 12, 1-13.