Miljkovic Jan Lj, Burger Nils, Gawel Justyna M, Mulvey John F, Norman Abigail A I, Nishimura Takanori, Tsujihata Yoshiyuki, Logan Angela, Sauchanka Olga, Caldwell Stuart T, Morris Jordan L, Prime Tracy A, Warrington Stefan, Prudent Julien, Bates Georgina R, Aksentijević Dunja, Prag Hiran A, James Andrew M, Krieg Thomas, Hartley Richard C, Murphy Michael P
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK.
School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK.
Redox Biol. 2022 Sep;55:102429. doi: 10.1016/j.redox.2022.102429. Epub 2022 Aug 5.
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.
线粒体靶向的硫化氢供体被认为可通过释放硫化氢来减轻氧化损伤，从而预防急性缺血再灌注（IR）损伤。然而，目前的供体释放硫化氢的速度过慢，在再灌注后给药时无法发挥有效作用。为克服这一限制，我们在此开发了一种线粒体靶向剂MitoPerSulf，它能在线粒体内非常快速地释放硫化氢。MitoPerSulf能迅速被线粒体摄取，在其中与内源性硫醇反应生成一个释放硫化氢的过硫化物中间体。MitoPerSulf对小鼠心脏IR损伤具有急性保护作用，这是由于急性生成的硫化氢抑制了细胞色素c氧化酶的呼吸作用，从而通过降低膜电位来防止线粒体超氧化物的产生。能快速生成硫化氢的线粒体靶向剂是一类用于急性治疗IR损伤的新型疗法。
