TY  - JOUR
AU  - Atkinson, J.
AU  - Kapralov, A.A.
AU  - Yanamala, N.
AU  - Tyurina, Y.Y.
AU  - Amoscato, A.A.
AU  - Pearce, L.
AU  - Peterson, J.
AU  - Huang, Z.
AU  - Jiang, J.
AU  - Samhan-Arias, A.K.
AU  - Maeda, A.
AU  - Feng, W.
AU  - Wasserloos, K.
AU  - Belikova, N.A.
AU  - Tyurin, V.A.
AU  - Wang, H.
AU  - Fletcher, J.
AU  - Wang, Y.
AU  - Vlasova, Il.
AU  - Klein-Seetharaman, J.
AU  - Stoyanovsky, D.A.
AU  - Bayir, H.
AU  - Pitt, B.R.
AU  - Epperly, M.W.
AU  - Greenberger, J.S.
AU  - Kagan, V.E.
TI  - A mitochondrial-targeted inhibitor of cytochrorme c peroxidase mitigates radiation-induced death
JO  - Nature Communications
VL  - 2
SN  - 2041-1723
CY  - London
PB  - Nature Publishing Group
M1  - PreJuSER-19623
SP  - 497
PY  - 2011
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 1 h before through 24 h after the irradiation.
KW  - Animals
KW  - Cell Death: drug effects
KW  - Cell Death: radiation effects
KW  - Cytochrome-c Peroxidase: antagonists & inhibitors
KW  - Electron Spin Resonance Spectroscopy
KW  - Enzyme Inhibitors: chemistry
KW  - Enzyme Inhibitors: pharmacology
KW  - Female
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mitochondria: drug effects
KW  - Mitochondria: enzymology
KW  - Models, Molecular
KW  - Molecular Dynamics Simulation
KW  - Radiation-Protective Agents: chemistry
KW  - Radiation-Protective Agents: pharmacology
KW  - Enzyme Inhibitors (NLM Chemicals)
KW  - Radiation-Protective Agents (NLM Chemicals)
KW  - Cytochrome-c Peroxidase (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:21988913
UR  - <Go to ISI:>//WOS:000296787300010
DO  - DOI:10.1038/ncomms1499
UR  - https://juser.fz-juelich.de/record/19623
ER  -