Redox Biology (Sep 2022)
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
Affiliations
- Jan Lj. Miljkovic
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK
- Nils Burger
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK
- Justyna M. Gawel
- School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK
- John F. Mulvey
- Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
- Abigail A.I. Norman
- School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK
- Takanori Nishimura
- Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK; Innovative Biology Laboratories, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 251-8555, Japan
- Yoshiyuki Tsujihata
- Innovative Biology Laboratories, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 251-8555, Japan
- Angela Logan
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK
- Olga Sauchanka
- Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
- Stuart T. Caldwell
- School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK
- Jordan L. Morris
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK
- Tracy A. Prime
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK
- Stefan Warrington
- School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK
- Julien Prudent
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK
- Georgina R. Bates
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK
- Dunja Aksentijević
- 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
- Hiran A. Prag
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
- Andrew M. James
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK
- Thomas Krieg
- Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
- Richard C. Hartley
- School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK; Corresponding author. School of Chemitry, University of Glasgow, Glasgow, G12 8QQ, UK.
- Michael P. Murphy
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK; Corresponding author. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, CB2 0XY, UK.
- Journal volume & issue
-
Vol. 55
p. 102429
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.
