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2-氧代戊二酸载体对酒精摄入的敏感性导致线粒体谷胱甘肽耗竭。

Sensitivity of the 2-oxoglutarate carrier to alcohol intake contributes to mitochondrial glutathione depletion.

作者信息

Coll Olga, Colell Anna, García-Ruiz Carmen, Kaplowitz Neil, Fernández-Checa J C

机构信息

Liver Unit, Hospital Clínic i Provincial, Institut de Malalties Digestives, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Consejo Superior de Investigaciones Científicas, Barcelona, Spain.

出版信息

Hepatology. 2003 Sep;38(3):692-702. doi: 10.1053/jhep.2003.50351.

Abstract

The mitochondrial pool of reduced glutathione (mGSH) is known to play a protective role against liver injury and cytokine-mediated cell death. However, the identification of the mitochondrial carriers involved in its transport in hepatocellular mitochondria remains unestablished. In this study, we show that the functional expression of the 2-oxoglutarate carrier from HepG2 cells in mitochondria from Xenopus laevis oocytes conferred a reduced glutathione (GSH) transport activity that was inhibited by phenylsuccinate, a specific inhibitor of the carrier. In addition, the mitochondrial transport of GSH and 2-oxoglutarate in isolated mitochondria from rat liver exhibited mutual competition and sensitivity to glutamate and phenylsuccinate. Interestingly, the kinetics of 2-oxoglutarate transport in rat liver mitochondria displayed a single Michaelis-Menten component with a Michaelis constant of 3.1 +/- 0.3 mmol/L and maximum velocity of 1.9 +/- 0.1 nmol/mg protein/25 seconds. Furthermore, the initial rate of 2-oxoglutarate was reduced in mitochondria from alcohol-fed rat livers, an effect that was not accompanied by an alcohol-induced decrease in the 2-oxoglutarate messenger RNA levels but rather by changes in mitochondrial membrane dynamics induced by alcohol. The fluidization of mitochondria by the fluidizing agent 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl) (A(2)C) restored the initial transport rate of both GSH and 2-oxoglutarate. Finally, these changes were reproduced in normal liver mitochondria enriched in cholesterol where the fluidization of cholesterol-enriched mitochondria with A(2)C restored the order membrane parameter and the mitochondrial 2-oxoglutarate uptake. In conclusion, these findings provide unequivocal evidence for 2-oxoglutarate as a GSH carrier and its sensitivity to membrane dynamics perturbation contributes in part to the alcohol-induced mGSH depletion.

摘要

已知还原型谷胱甘肽的线粒体池(mGSH)在抵抗肝损伤和细胞因子介导的细胞死亡中发挥保护作用。然而,肝细胞线粒体中参与其转运的线粒体载体尚未确定。在本研究中,我们发现来自HepG2细胞的2-氧代戊二酸载体在非洲爪蟾卵母细胞的线粒体中的功能性表达赋予了还原型谷胱甘肽(GSH)转运活性,该活性受到该载体的特异性抑制剂苯基琥珀酸盐的抑制。此外,大鼠肝脏分离线粒体中GSH和2-氧代戊二酸的线粒体转运表现出相互竞争以及对谷氨酸和苯基琥珀酸盐的敏感性。有趣的是,大鼠肝脏线粒体中2-氧代戊二酸转运的动力学显示出单一的米氏成分,米氏常数为3.1±0.3 mmol/L,最大速度为1.9±0.1 nmol/mg蛋白质/25秒。此外,酒精喂养的大鼠肝脏线粒体中2-氧代戊二酸的初始速率降低,这种效应并非伴随着酒精诱导的2-氧代戊二酸信使RNA水平的降低,而是由酒精诱导的线粒体膜动力学变化引起的。流化剂2-(2-甲氧基乙氧基)乙基8-(顺式-2-正辛基环丙基)(A(2)C)使线粒体流化恢复了GSH和2-氧代戊二酸的初始转运速率。最后,在富含胆固醇的正常肝脏线粒体中也出现了这些变化,用A(2)C使富含胆固醇的线粒体流化恢复了有序膜参数和线粒体对2-氧代戊二酸的摄取。总之,这些发现为2-氧代戊二酸作为GSH载体提供了明确证据,其对膜动力学扰动的敏感性部分导致了酒精诱导的mGSH耗竭。

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