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

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  • 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.
    Department of Chemistry & Centre for Biotechnology Brock University)

  • 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15261, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    Graduate School of Public Health, University of Pittsburgh, 201 North Craig Street, Suite 325 Sterling Plaza, Pittsburgh, Pennsylvania 15213, 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.
    Department of Chemistry & Centre for Biotechnology Brock University)

  • 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.
    Department of Chemistry & Centre for Biotechnology Brock University)

  • 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, Pittsburgh, Pennsylvania 15219, USA.
    School of Medicine, University of Pittsburgh)

  • 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.
    University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Rm. 533, Pittsburgh, Pennsylvania 15232, 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.
    University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Rm. 533, Pittsburgh, Pennsylvania 15232, 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.
    University of Pittsburgh, 3501 Fifth Avenue, BST3 Rm. 2051, Pittsburgh, Pennsylvania 15219, USA.)

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.

Suggested Citation

  • 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 M, 2011. "A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1499
    DOI: 10.1038/ncomms1499
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