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

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.; Maeda, Akihiro; Feng, Weihong; Wasserloos, Karla; Belikova, Natalia A.; Tyurin, Vladimir A.; Wang, Hong; Fletcher, Jackie; Wang, Yongsheng; Vlasova, Irina I.; Klein-Seetharaman, Judith; Stoyanovsky, Detcho A.; Bayîr, Hülya; Pitt, Bruce R.; Epperly, Michael W.; Greenberger, Joel S.; Kagan, Valerian E.

doi:10.1038/ncomms1499

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

10 11 2011
By Atkinson, Jeffrey ; Kapralov, Alexandr A. ; Yanamala, Naveena ; ...
http://dx.doi.org/10.1038/ncomms1499
Source: Nat Commun. 2:497

[PDF-1.62 MB]

English

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Alternative Title:

Nat Commun
Personal Author:

Atkinson, Jeffrey ; Kapralov, Alexandr A. ; Yanamala, Naveena ; Tyurina, Yulia Y. ; Amoscato, Andrew A. ; ... More +

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. ; Maeda, Akihiro ; Feng, Weihong ; Wasserloos, Karla ; Belikova, Natalia A. ; Tyurin, Vladimir A. ; Wang, Hong ; Fletcher, Jackie ; Wang, Yongsheng ; Vlasova, Irina I. ; Klein-Seetharaman, Judith ; Stoyanovsky, Detcho A. ; Bayîr, Hülya ; Pitt, Bruce R. ; Epperly, Michael W. ; Greenberger, Joel S. ; Kagan, Valerian E. Less -
Description:

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.
Subjects:

[+]

Animals Cell Death Cytochrome-c Peroxidase Electron Spin Resonance Spectroscopy Enzyme Inhibitors Female Mice Mice, Inbred C57BL Mitochondria Models, Molecular Molecular Dynamics Simulation Radiation-Protective Agents
Source:

Nat Commun. 2:497
Pubmed ID:

21988913
Pubmed Central ID:

PMC3557495
Document Type:

Journal Article
Funding:

R01 OH008282/OH/NIOSH CDC HHSUnited States/ ; R01 HL094488/HL/NHLBI NIH HHSUnited States/ ; R01 CA119927/CA/NCI NIH HHSUnited States/ ; R01 HL070755/HL/NHLBI NIH HHSUnited States/ ; U19 AI068021/AI/NIAID NIH HHSUnited States/ ; ... More +

R01 OH008282/OH/NIOSH CDC HHSUnited States/ ; R01 HL094488/HL/NHLBI NIH HHSUnited States/ ; R01 CA119927/CA/NCI NIH HHSUnited States/ ; R01 HL070755/HL/NHLBI NIH HHSUnited States/ ; U19 AI068021/AI/NIAID NIH HHSUnited States/ ; R03 TW007320/TW/FIC NIH HHSUnited States/ Less -
Collection(s):

CDC Public Access
Main Document Checksum:

[+]

urn:sha256:5feff3b2ee700d1a27ed11c7656377c3cad9df02d452ee6387eb73548f17b626
Download URL:

https://stacks.cdc.gov/view/cdc/41875/cdc_41875_DS1.pdf
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