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; Valerian E. Kagan

doi:10.1038/ncomms1499

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, Valerian E. Kagan

Research output: Contribution to journal › Article › peer-review

95 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 language	English (US)
Article number	497
Journal	Nature communications
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/ncomms1499
State	Published - 2011
Externally published	Yes

ASJC Scopus subject areas

General
General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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Atkinson, J., Kapralov, A. A., Yanamala, N., Tyurina, Y. Y., Amoscato, A. A., Pearce, L., Peterson, J., Huang, Z., Jiang, J., Samhan-Arias, A. K., Maeda, A., Feng, W., Wasserloos, K., Belikova, N. A., Tyurin, V. A., Wang, H., Fletcher, J., Wang, Y., Vlasova, I. I., ... Kagan, V. E. (2011). A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death. Nature communications, 2(1), Article 497. https://doi.org/10.1038/ncomms1499

Atkinson, J, Kapralov, AA, Yanamala, N, Tyurina, YY, Amoscato, AA, Pearce, L, Peterson, J, Huang, Z, Jiang, J, Samhan-Arias, AK, Maeda, A, Feng, W, Wasserloos, K, Belikova, NA, Tyurin, VA, Wang, H, Fletcher, J, Wang, Y, Vlasova, II, Klein-Seetharaman, J, Stoyanovsky, DA, Bayîr, H, Pitt, BR, Epperly, MW, Greenberger, JS & Kagan, VE 2011, 'A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death', Nature communications, vol. 2, no. 1, 497. https://doi.org/10.1038/ncomms1499

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title = "A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death",

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.",

author = "Jeffrey Atkinson and Kapralov, \{Alexandr A.\} and Naveena Yanamala and Tyurina, \{Yulia Y.\} and Amoscato, \{Andrew A.\} and Linda Pearce and Jim Peterson and Zhentai Huang and Jianfei Jiang and Samhan-Arias, \{Alejandro K.\} and Akihiro Maeda and Weihong Feng and Karla Wasserloos and Belikova, \{Natalia A.\} and Tyurin, \{Vladimir A.\} and Hong Wang and Jackie Fletcher and Yongsheng Wang and Vlasova, \{Irina I.\} and Judith Klein-Seetharaman and Stoyanovsky, \{Detcho A.\} and H{\"u}lya Bay{\^i}r and Pitt, \{Bruce R.\} and Epperly, \{Michael W.\} and Greenberger, \{Joel S.\} and Kagan, \{Valerian E.\}",

year = "2011",

doi = "10.1038/ncomms1499",

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AU - Atkinson, Jeffrey

AU - Kapralov, Alexandr A.

AU - Yanamala, Naveena

AU - Tyurina, Yulia Y.

AU - Amoscato, Andrew A.

AU - Pearce, Linda

AU - Peterson, Jim

AU - Huang, Zhentai

AU - Jiang, Jianfei

AU - Samhan-Arias, Alejandro K.

AU - Maeda, Akihiro

AU - Feng, Weihong

AU - Wasserloos, Karla

AU - Belikova, Natalia A.

AU - Tyurin, Vladimir A.

AU - Wang, Hong

AU - Fletcher, Jackie

AU - Wang, Yongsheng

AU - Vlasova, Irina I.

AU - Klein-Seetharaman, Judith

AU - Stoyanovsky, Detcho A.

AU - Bayîr, Hülya

AU - Pitt, Bruce R.

AU - Epperly, Michael W.

AU - Greenberger, Joel S.

AU - Kagan, Valerian E.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

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