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

Jeffrey Atkinson, Alexandr A. Kapralov, Naveena Yanamala, Yulia Y. Tyurina, Andrew A. Amoscato, Linda Pearce, Jim Peterson, Zhentai Huang, Jianfei Jiang, Alejandro K. Samhan-Arias, Akihiro Maeda, Weihong Feng, Karla Wasserloos, Natalia A. Belikova, Vladimir A. Tyurin, Hong Wang, Jackie Fletcher, Yongsheng Wang, Irina I. Vlasova, Judith Klein-SeetharamanDetcho A. Stoyanovsky, Hülya Bayîr, Bruce R. Pitt, Michael W. Epperly, Joel S. Greenberger, Valerian E. Kagan

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

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 1ĝ€‰h before through 24ĝ€‰h after the irradiation.

Original languageEnglish (US)
Article number497
JournalNature communications
Volume2
Issue number1
DOIs
StatePublished - 2011
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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