Rapid and selective generation of HS within mitochondria protects against cardiac ischemia-reperfusion injury.

Mitochondria-targeted HS donors are thought to protect against acute ischemia-reperfusion (IR) injury by releasing HS that decreases oxidative damage. However, the rate of HS release by current donors is too slow to be effective upon administration following reperfusion. To overcome this limitation here we develop a mitochondria-targeted agent, MitoPerSulf that very rapidly releases HS within mitochondria. MitoPerSulf is quickly taken up by mitochondria, where it reacts with endogenous thiols to generate a persulfide intermediate that releases HS. MitoPerSulf is acutely protective against cardiac IR injury in mice, due to the acute generation of HS that inhibits respiration at cytochrome c oxidase thereby preventing mitochondrial superoxide production by lowering the membrane potential. Mitochondria-targeted agents that rapidly generate HS are a new class of therapy for the acute treatment of IR injury.