Hydrogen Sulfide Increases Glutathione Production and Suppresses Oxidative Stress in Mitochondria

Hydrogen sulfide (H 2 S) is a synaptic modulator as well as a neuroprotectant in the brain. We recently showed that H 2 S 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 H 2 S 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 H 2 S is even greater by fourfold under oxidative stress by glutamate. H 2 S reinstated GSH levels in the fetal brain decreased by ischemia/reperfusion in utero . In addition, Neuro2a cells expressing a mitochondrial H 2 S-producing enzyme, 3-mercaptopyruvate sulfurtransferase (3MST), along with cysteine aminotransferase (CAT), showed significant resistance to oxidative stress. The present study shows that H 2 S protects cells from oxidative stress by two mechanisms. It enhances the production of GSH by enhancing cystine/cysteine transporters and redistributes GSH to mitochondria. H 2 S produced in mitochondria also may directly suppress oxidative stress. It provides a new mechanism of neuroprotection from oxidative stress by H 2 S. Antioxid. Redox Signal. 12, 1–13.