Rapid and selective generation of H(2)S within mitochondria protects against cardiac ischemia-reperfusion injury

Mitochondria-targeted H(2)S donors are thought to protect against acute ischemia-reperfusion (IR) injury by releasing H(2)S that decreases oxidative damage. However, the rate of H(2)S 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 H(2)S within mitochondria. MitoPerSulf is quickly taken up by mitochondria, where it reacts with endogenous thiols to generate a persulfide intermediate that releases H(2)S. MitoPerSulf is acutely protective against cardiac IR injury in mice, due to the acute generation of H(2)S that inhibits respiration at cytochrome c oxidase thereby preventing mitochondrial superoxide production by lowering the membrane potential. Mitochondria-targeted agents that rapidly generate H(2)S are a new class of therapy for the acute treatment of IR injury.