A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death

被引：85

作者：

Atkinson, Jeffrey ^{[1
,2
,3
,4
]}

Kapralov, Alexandr A. ^{[1
,2
,5
,6
]}

Yanamala, Naveena ^{[1
,2
,7
]}

Tyurina, Yulia Y. ^{[1
,2
,5
,6
]}

Amoscato, Andrew A. ^{[1
,2
,5
,6
]}

Pearce, Linda ^{[5
,6
]}

Peterson, Jim ^{[5
,6
]}

Huang, Zhentai ^{[1
,2
,5
,6
]}

Jiang, Jianfei ^{[2
,5
,6
]}

Samhan-Arias, Alejandro K. ^{[1
,2
,5
,6
]}

Maeda, Akihiro ^{[1
,2
,5
,6
]}

Feng, Weihong ^{[1
,2
,5
,6
]}

Wasserloos, Karla ^{[5
,6
]}

Belikova, Natalia A. ^{[1
,2
,5
,6
]}

Tyurin, Vladimir A. ^{[1
,2
,5
,6
]}

Wang, Hong ^{[1
,2
,8
]}

Fletcher, Jackie ^{[1
,2
,3
,4
]}

Wang, Yongsheng ^{[1
,2
,3
,4
]}

Vlasova, Irina I. ^{[1
,2
,5
,6
]}

Klein-Seetharaman, Judith ^{[7
]}

Stoyanovsky, Detcho A. ^{[1
,2
,5
,6
]}

Bayir, Huelya ^{[1
,2
,5
,6
,9
]}

Pitt, Bruce R. ^{[5
,6
]}

Epperly, Michael W. ^{[1
,2
,10
]}

Greenberger, Joel S. ^{[1
,2
,10
]}

Kagan, Valerian E. ^{[1
,2
,5
,6
]}

机构：

[1] Univ Pittsburgh, Ctr Free Rad & Antioxidant Hlth, Pittsburgh, PA 15219 USA

[2] Univ Pittsburgh, Ctr Med Countermeasures Radiat, Pittsburgh, PA 15219 USA

[3] Brock Univ, Dept Chem, St Catharines, ON L2S 3A1, Canada

[4] Brock Univ, Ctr Biotechnol, St Catharines, ON L2S 3A1, Canada

[5] Univ Pittsburgh, Dept Environm Hlth, Pittsburgh, PA 15219 USA

[6] Univ Pittsburgh, Dept Occupat Hlth, Pittsburgh, PA 15219 USA

[7] Univ Pittsburgh, Dept Biol Struct, Pittsburgh, PA 15261 USA

[8] Univ Pittsburgh, Dept Biostat, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA

[9] Univ Pittsburgh, Dept Crit Care Med, Sch Med, Pittsburgh, PA 15261 USA

[10] Univ Pittsburgh, Dept Radiat Oncol, Inst Canc, Pittsburgh, PA 15232 USA

来源：

NATURE COMMUNICATIONS | 2011年 / 2卷

关键词：

ALKALINE TRANSITION; INDUCED APOPTOSIS; CARDIOLIPIN; P53; INTRAPERITONEAL; SENSITIVITY; IDENTIFICATION; INJURY; DAMAGE; CELLS;

D O I：

10.1038/ncomms1499

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：9

共 45 条

[1]

Peroxidase activity and structural transitions of cytochrome c bound to cardiolipin-containing membranes [J].