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

Details

• Alternative Title:
  Nat Commun
• Personal Author:
  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.
• 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

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• 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/ ; R03 TW007320/TW/FIC NIH HHSUnited States/
• Volume:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:5feff3b2ee700d1a27ed11c7656377c3cad9df02d452ee6387eb73548f17b626
• Download URL:
  https://stacks.cdc.gov/view/cdc/41875/cdc_41875_DS1.pdf
• File Type:
  [PDF - 1.62 MB ]