A Mitochondria-Targeted Inhibitor of Cytochrome C Peroxidase Mitigates Radiation-Induced Death

Details

• Personal Author:
  Amoscato AA ; Atkinson J ; Bayîr H ; Belikova NA ; Epperly MW ; Feng W ; Fletcher J ; Greenberger JS ; Huang Z ; Jiang J ; Kagan VE ; Kapralov AA ; Klein-Seetharaman J ; Maeda A ; Pearce L ; Peterson J ; Pitt BR ; Samhan-Arias AK ; Stoyanovsky DA ; Tyurin VA ; Tyurina YY ; Vlasova II ; Wang H ; Wang Y ; Wasserloos K ; Yanamala N
• 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 1h before through 24h after the irradiation. [Description provided by NIOSH]
• Subjects:
  Animals Occupational Health Radiation Safety
• Keywords:
  Animal Studies Biological Effects Cell Death Cellular Effects Ionizing Radiation Peroxidases Radiation Effects Radiation Exposure Radiation Properties Radioactive Materials Radionuclides

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• ISSN:
  2041-1723
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  2
• NIOSHTIC Number:
  nn:20053283
• Citation:
  Nat Commun 2011 Oct; 2:497
• Contact Point Address:
  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
• Email:
  kagan@pitt.edu
• Federal Fiscal Year:
  2012
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Nature Communications
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:40dbf8c6f548b21b939f19c90a35cfb7a6c791722f8c4ac7794296170e2b3de0ce3a1e3b145b4e91e714fab2223827aad2c45ca7bcb90e27f8250d9ead1c5356
• Download URL:
  https://stacks.cdc.gov/view/cdc/216074/cdc_216074_DS1.pdf
• File Type:
  [PDF - 1.14 MB ]