The brain is exquisitely sensitive to the lack of oxygen. Acute oxygen deprivation inhibits mitochondrial energy production impairing the cellular integrity. Although ischemic brain injury is a leading cause of morbidity and mortality, mechanism responsible for the ischemia-induced energy failure of the brain is incompletely understood. Hydrogen sulfide is an environmental hazard well known for its neurotoxicity. In mammalian cells, H2S is produced by the transsulfuration pathway and is oxidized in mitochondria by sulfide oxidation enzymes including sulfide quinone oxidoreductase (SQR). When oxygen is abundant, sulfide oxidation donates electrons to the mitochondrial electron transport chain (ETC), thereby promoting adenosine triphosphate (ATP) synthesis. In contrast, oxygen deprivation stimulates sulfide synthesis and hinders sulfide oxidation, leading to sulfide accumulation. Accumulated sulfide inhibits ETC complex IV during ischemia and aggravate reperfusion injury. Therefore, sulfide catabolism may play a pivotal role in the energy homeostasis during oxygen shortage and cellular injury upon reoxygenation. However, role of sulfide catabolism on the bioenergetics of the brain during acute oxygen deprivation has thus far attracted little attention. SQR is normally expressed at very low levels in the central nervous system, explaining the particularly slow rate of sulfide consumption in the brain. In preliminary studies, we observed that female mice had higher levels of SQR in the brain and were more resistant to hypoxia than male mice, whereas, knockdown of brain SQR increased the sensitivity of female mice to hypoxia. SQR overexpression in the brain of mice prevented neurologic dysfunction and death after global cerebral ischemia and reperfusion (I/R). Pharmacological sulfide scavengers prevented ETC dysfunction and improved energy production in human cells incubated in hypoxia or in the brains of mice subjected to cerebral ischemia. Based on these observations, we hypothesize that preventing sulfide accumulation in the brain either by enhanced sulfide oxidation or pharmacologic sulfide scavenger prevents ETC dysfunction during oxygen shortage and attenuates ischemia/reperfusion injury of the brain. To address this hypothesis, we propose: To determine the effects of enhanced sulfide oxidation on the severity of ischemic brain injury (Aim1), to characterize the role of endogenous sulfide catabolism in the mitochondrial function and response to ischemic brain injury (Aim 2), and to define the mechanism of the neuroprotective effects of sulfide oxidation and therapeutic potential of sulfide scavenging after cerebral I/R. (Aim 3). Proposed studies are anticipated to illuminate the critical role of sulfide in mitochondrial respiration and uncover a therapeutic potential of sulfide catabolism in ischemic brain injury.