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A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death

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Atkinson, Jeffrey, Kapralov, Alexandr A., Yanamala, Naveena, Tyurina, Yulia Y., Amoscato, Andrew A., Pearce, Linda, Peterson, Jim, Huang, Zhentai, Jiang, Jianfei, Samhan-Arias, Alejandro K. et al.
(2011) A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death. Nature Communications, 2 . Article: 497. doi:10.1038/ncomms1499 ISSN 2041-1723.

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Official URL: http://dx.doi.org/10.1038/ncomms1499

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Abstract

The risk of radionuclide release in terrorist acts or exposure of healthy tissue during radiotherapy demand potent radioprotectants/radiomitigators. Ionizing radiation induces cell death by initiating the selective peroxidation of cardiolipin in mitochondria by the peroxidase activity of its complex with cytochrome c leading to release of haemoprotein into the cytosol and commitment to the apoptotic program. Here we design and synthesize mitochondria-targeted triphenylphosphonium-conjugated imidazole-substituted oleic and stearic acids that blocked peroxidase activity of cytochrome c/cardiolipin complex by specifically binding to its haem-iron. We show that both compounds inhibit pro-apoptotic oxidative events, suppress cyt c release, prevent cell death, and protect mice against lethal doses of irradiation. Significant radioprotective/radiomitigative effects of imidazole-substituted oleic acid are observed after pretreatment of mice from 1 h before through 24 h after the irradiation.

Item Type: Journal Article
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016)
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine
Journal or Publication Title: Nature Communications
Publisher: Nature Publishing Group
ISSN: 2041-1723
Official Date: 11 October 2011
Dates:
DateEvent
11 October 2011Published
Volume: 2
Page Range: Article: 497
DOI: 10.1038/ncomms1499
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access

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