Rapid and selective generation of H2S within mitochondria protects against cardiac ischemia-reperfusion injury

Jan Lj Miljkovic; Nils Burger; Justyna M Gawel; John F Mulvey; Abigail A I Norman; Takanori Nishimura; Yoshiyuki Tsujihata; Angela Logan; Olga Sauchanka; Stuart T Caldwell; Jordan L Morris; Tracy A Prime; Stefan Warrington; Julien Prudent; Georgina R Bates; Dunja Aksentijević; Hiran A Prag; Andrew M James; Thomas Krieg; Richard C Hartley; Michael P Murphy

doi:10.1016/j.redox.2022.102429

Rapid and selective generation of H₂S within mitochondria protects against cardiac ischemia-reperfusion injury

Redox Biol. 2022 Sep:55:102429. doi: 10.1016/j.redox.2022.102429. Epub 2022 Aug 5.

Authors

Jan Lj Miljkovic¹, Nils Burger¹, Justyna M Gawel², John F Mulvey³, Abigail A I Norman², Takanori Nishimura⁴, Yoshiyuki Tsujihata⁵, Angela Logan¹, Olga Sauchanka³, Stuart T Caldwell², Jordan L Morris¹, Tracy A Prime¹, Stefan Warrington², Julien Prudent¹, Georgina R Bates¹, Dunja Aksentijević⁶, Hiran A Prag⁷, Andrew M James¹, Thomas Krieg³, Richard C Hartley⁸, Michael P Murphy⁹

Affiliations

¹ MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK.
² School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK.
³ Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.
⁴ Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK; Innovative Biology Laboratories, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 251-8555, Japan.
⁵ Innovative Biology Laboratories, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 251-8555, Japan.
⁶ Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
⁷ MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.
⁸ School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK. Electronic address: Richard.Hartley@glasgow.ac.uk.
⁹ MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK. Electronic address: mpm@mrc-mbu.cam.ac.uk.

Abstract

Mitochondria-targeted H₂S donors are thought to protect against acute ischemia-reperfusion (IR) injury by releasing H₂S that decreases oxidative damage. However, the rate of H₂S 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 H₂S within mitochondria. MitoPerSulf is quickly taken up by mitochondria, where it reacts with endogenous thiols to generate a persulfide intermediate that releases H₂S. MitoPerSulf is acutely protective against cardiac IR injury in mice, due to the acute generation of H₂S that inhibits respiration at cytochrome c oxidase thereby preventing mitochondrial superoxide production by lowering the membrane potential. Mitochondria-targeted agents that rapidly generate H₂S are a new class of therapy for the acute treatment of IR injury.

Keywords: Hydrogen sulfide donors; Ischemia-reperfusion injury; Mitochondria; Mitochondria targeting; Reverse electron transport (RET).

Abstract

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