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-Seetharaman, Detcho A. Stoyanovsky, Hülya Bayîr, Bruce R. Pitt, Michael W. Epperly, Joel S. Greenberger and Valerian E. Kagan ()
Additional contact information
Jeffrey Atkinson: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Alexandr A. Kapralov: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Naveena Yanamala: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Yulia Y. Tyurina: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Andrew A. Amoscato: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Linda Pearce: University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, Pittsburgh, Pennsylvania 15219, USA.
Jim Peterson: University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, Pittsburgh, Pennsylvania 15219, USA.
Zhentai Huang: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Jianfei Jiang: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Alejandro K. Samhan-Arias: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Akihiro Maeda: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Weihong Feng: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Karla Wasserloos: University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, Pittsburgh, Pennsylvania 15219, USA.
Natalia A. Belikova: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Vladimir A. Tyurin: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Hong Wang: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Jackie Fletcher: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Yongsheng Wang: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Irina I. Vlasova: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Judith Klein-Seetharaman: University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15261, USA.
Detcho A. Stoyanovsky: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Hülya Bayîr: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Bruce R. Pitt: University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, Pittsburgh, Pennsylvania 15219, USA.
Michael W. Epperly: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Joel S. Greenberger: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.
Valerian E. Kagan: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219, USA.

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1499

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