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

Miljkovic, J. L. et al. (2022) Rapid and selective generation of H2S within mitochondria protects against cardiac ischemia-reperfusion injury. Redox Biology, 55, 102429. (doi: 10.1016/j.redox.2022.102429) (PMID:35961099) (PMCID:PMC9382561)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Caldwell, Dr Stuart and Warrington, Dr Stefan and Hartley, Professor Richard and Norman, Miss Abigail
Authors: Miljkovic, J. L., Burger, N., Gawel, J. M., Mulvey, J. F., Norman, A. A. I., Nishimura, T., Tsujihata, Y., Logan, A., Sauchanka, O., Caldwell, S. T., Morris, J. L., Prime, T. A., Warrington, S., Prudent, J., Bates, G. R., Aksentijeviü, D., Prag, H. A., James, A. M., Krieg, T., Hartley, R. C., and Murphy, M. P.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Redox Biology
Publisher:Elsevier
ISSN:2213-2317
ISSN (Online):2213-2317
Published Online:05 August 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Redox Biology 55: 102429
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172617Exploring mitochondrial metabolism in health and disease using targeted biological chemistryRichard HartleyWellcome Trust (WELLCOTR)110158/Z/15/ZChemistry
309730Exploring mitochondrial metabolism in health and disease using targeted biological chemistryRichard HartleyWellcome Trust (WELLCOTR)220257/B/20/ZChemistry
165401Developing chemical mass spectrometry probes to assess the production of reactive oxygen species in vivoRichard HartleyBiotechnology and Biological Sciences Research Council (BBSRC)BB/I012826/1Chemistry