title: A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death.
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.
authors: Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Bridgeside Point, Pennsylvania 15219, USA.
authors: Jeffrey
authors: J
authors: Atkinson
authors: Alexandr A
authors: AA
authors: Kapralov
authors: Naveena
authors: N
authors: Yanamala
authors: Yulia Y
authors: YY
authors: Tyurina
authors: Andrew A
authors: AA
authors: Amoscato
authors: Linda
authors: L
authors: Pearce
authors: Jim
authors: J
authors: Peterson
authors: Zhentai
authors: Z
authors: Huang
authors: Jianfei
authors: J
authors: Jiang
authors: Alejandro K
authors: AK
authors: Samhan-Arias
authors: Akihiro
authors: A
authors: Maeda
authors: Weihong
authors: W
authors: Feng
authors: Karla
authors: K
authors: Wasserloos
authors: Natalia A
authors: NA
authors: Belikova
authors: Vladimir A
authors: VA
authors: Tyurin
authors: Hong
authors: H
authors: Wang
authors: Jackie
authors: J
authors: Fletcher
authors: Yongsheng
authors: Y
authors: Wang
authors: Irina I
authors: II
authors: Vlasova
authors: Judith
authors: J
authors: Klein-Seetharaman
authors: Detcho A
authors: DA
authors: Stoyanovsky
authors: Hülya
authors: H
authors: Bayîr
authors: Bruce R
authors: BR
authors: Pitt
authors: Michael W
authors: MW
authors: Epperly
authors: Joel S
authors: JS
authors: Greenberger
authors: Valerian E
authors: VE
authors: Kagan
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000528:radiation effects; D003578:Cytochrome-c Peroxidase / Q000037:antagonists & inhibitors*; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011837:Radiation-Protective Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011837:Radiation-Protective Agents; D003578:Cytochrome-c Peroxidase