A mitochondrial-targeted inhibitor of cytochrorme c peroxidase mitigates radiation-induced death

Atkinson, J.; Jiang, J.; Kapralov, A.A.; Epperly, M.W.; Tyurina, Y.Y.; Huang, Z.; Wasserloos, K.; Vlasova, Il.; Wang, Y.; Amoscato, A.A.; Fletcher, J.; Feng, W.; Bayir, H.; Belikova, N.A.; Peterson, J.; Stoyanovsky, D.A.; Samhan-Arias, A.K.; Yanamala, N.; Greenberger, J.S.; Maeda, A.; Tyurin, V.A.; Klein-Seetharaman, J.; Kagan, V.E.; Wang, H.; Pearce, L.; Pitt, B.R.

doi:10.1038/ncomms1499

Journal Article

PreJuSER-19623

A mitochondrial-targeted inhibitor of cytochrorme c peroxidase mitigates radiation-induced death

Atkinson, J. ; Kapralov, A. A. ; Yanamala, N. ; Tyurina, Y. Y. ; Amoscato, A. A. ; Pearce, L. ; Peterson, J. ; Huang, Z. ; Jiang, J. ; Samhan-Arias, A. K. ; Maeda, A. ; Feng, W. ; Wasserloos, K. ; Belikova, N. A. ; Tyurin, V. A. ; Wang, H. ; Fletcher, J. ; Wang, Y. ; Vlasova, I. ; Klein-Seetharaman, J.FZJ* ; Stoyanovsky, D. A. ; Bayir, H. ; Pitt, B. R. ; Epperly, M. W. ; Greenberger, J. S. ; Kagan, V. E.

2011
Nature Publishing Group London

Nature Communications 2, 497 (2011) [10.1038/ncomms1499]

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Please use a persistent id in citations: http://hdl.handle.net/2128/24486 doi:10.1038/ncomms1499

Abstract: 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.

Keyword(s): Animals (MeSH) ; Cell Death: drug effects (MeSH) ; Cell Death: radiation effects (MeSH) ; Cytochrome-c Peroxidase: antagonists & inhibitors (MeSH) ; Electron Spin Resonance Spectroscopy (MeSH) ; Enzyme Inhibitors: chemistry (MeSH) ; Enzyme Inhibitors: pharmacology (MeSH) ; Female (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mitochondria: drug effects (MeSH) ; Mitochondria: enzymology (MeSH) ; Models, Molecular (MeSH) ; Molecular Dynamics Simulation (MeSH) ; Radiation-Protective Agents: chemistry (MeSH) ; Radiation-Protective Agents: pharmacology (MeSH) ; Enzyme Inhibitors ; Radiation-Protective Agents ; Cytochrome-c Peroxidase ; J