%0 Journal Article
%A Atkinson, J.
%A Kapralov, A.A.
%A Yanamala, N.
%A Tyurina, Y.Y.
%A Amoscato, A.A.
%A Pearce, L.
%A Peterson, J.
%A Huang, Z.
%A Jiang, J.
%A Samhan-Arias, A.K.
%A Maeda, A.
%A Feng, W.
%A Wasserloos, K.
%A Belikova, N.A.
%A Tyurin, V.A.
%A Wang, H.
%A Fletcher, J.
%A Wang, Y.
%A Vlasova, Il.
%A Klein-Seetharaman, J.
%A Stoyanovsky, D.A.
%A Bayir, H.
%A Pitt, B.R.
%A Epperly, M.W.
%A Greenberger, J.S.
%A Kagan, V.E.
%T A mitochondrial-targeted inhibitor of cytochrorme c peroxidase mitigates radiation-induced death
%J Nature Communications
%V 2
%@ 2041-1723
%C London
%I Nature Publishing Group
%M PreJuSER-19623
%P 497
%D 2011
%X 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.
%K Animals
%K Cell Death: drug effects
%K Cell Death: radiation effects
%K Cytochrome-c Peroxidase: antagonists & inhibitors
%K Electron Spin Resonance Spectroscopy
%K Enzyme Inhibitors: chemistry
%K Enzyme Inhibitors: pharmacology
%K Female
%K Mice
%K Mice, Inbred C57BL
%K Mitochondria: drug effects
%K Mitochondria: enzymology
%K Models, Molecular
%K Molecular Dynamics Simulation
%K Radiation-Protective Agents: chemistry
%K Radiation-Protective Agents: pharmacology
%K Enzyme Inhibitors (NLM Chemicals)
%K Radiation-Protective Agents (NLM Chemicals)
%K Cytochrome-c Peroxidase (NLM Chemicals)
%K J (WoSType)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:21988913
%U <Go to ISI:>//WOS:000296787300010
%R 10.1038/ncomms1499
%U https://juser.fz-juelich.de/record/19623