Mitochondrial stress protein recognition of inactivated dehydrogenases during mammalian cell death

被引:29
作者
Bruschi, SA [1 ]
Lindsay, JG
Crabb, JW
机构
[1] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA
[2] Adirondack Biomed Res Inst, Lake Placid, NY 12946 USA
[3] Univ Glasgow, Inst Biomed & Life Sci, Div Biochem & Mol Biol, Glasgow G12 8QQ, Lanark, Scotland
关键词
D O I
10.1073/pnas.95.23.13413
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
07 ; 0710 ; 09 ;
摘要
The mammalian renal toxicant tetrafluoroethylcysteine (TFEC) is metabolized to a reactive intermediate that covalently modifies the lysine residues of a select group of mitochondrial proteins, forming difluorothioamidyl lysine protein adducts, Cellular damage is initiated by this process and cell death ensues, NH2-terminal sequence analysis of purified mitochondrial proteins containing difluorothioamidyl lysine adducts identified the lipoamide succinyltransferase and dihydrolipoamide dehydrogenase subunits of the alpha-ketoglutarate dehydrogenase complex (alpha KGDH), a key regulatory component of oxidative metabolism as targets for TFEC action. Adduct formation resulted in marked inhibition of alpha KGDH enzymatic activity, whereas the related pyruvate dehydrogenase complex was unmodified by TFEC and its activity was not inhibited in vivo. Covalent modification of alpha KGDH subunits also resulted in interactions with mitochondrial chaperonin HSP60 in vivo and with HSP60 and mitochondrial HSP70 in vitro. These observations confirm the role of mammalian stress proteins in the recognition of abnormal proteins and provide supporting evidence for reactive metabolite-induced cell death by modification of critical protein targets.
引用
收藏
页码:13413 / 13418
页数:6
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