Contribution of liver mitochondrial membrane-bound glutathione transferase to mitochondrial permeability transition pores
Contribution of liver mitochondrial membrane-bound glutathione transferase to mitochondrial permeability transition pores
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DOI：
10.1016/j.taap.2008.11.016
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发表时间：
2009-02-15
影响因子：
3.8
通讯作者：
Aniya, Yoko
中科院分区：
文献类型：
--
作者：
Hossain, Quazi Sohel;Ulziikhishig, Enkhbaatar;Aniya, Yoko
我们最近报道了大鼠肝脏线粒体膜谷胱甘肽转移酶（mtMGST1）被s -谷胱甘肽酰化激活，激活的mtMGST1有助于线粒体通透性转移（MPT）孔和细胞色素c从线粒体释放[Lee， K.K., Shimoji， M., Quazi, s.h., Sunakawa， H., Aniya， Y., 2008]。谷胱甘肽转移酶在大鼠肝脏线粒体膜中的新功能：对线粒体释放细胞色素c的作用。Toxcol。达成。药物杂志》232。109 - 118年)。在本研究中，我们研究了活性氧（ROS）、没食子酸（GA）和GST抑制剂对mtMGST1和MITE的影响，当用GA孵育大鼠肝脏线粒体时，mtMGSTI活性增加约3倍，并被抗氧化酶和单线态氧猝灭剂（包括1,4-重氮杂环[2,2,2]辛烷（DABCO））抑制。ga介导的mtMGST1活化可被单宁酸、血红素和环孢素A （CsA）等GST抑制剂阻止。此外，GA诱导线粒体肿胀，GST抑制剂也能抑制线粒体肿胀，而MPT抑制剂CsA不能抑制线粒体肿胀。ADP和苯丙酸。GA还能从线粒体中释放细胞色素c， DABCO能完全抑制，GST抑制剂能适度抑制，CsA能部分抑制。Ca2+介导的线粒体肿胀和细胞色素c释放被MPT抑制剂抑制，而不被GST抑制剂抑制。GA处理线粒体后，分离线粒体外膜，mtMGST1活性显著升高，并观察到mtMGST1的低聚物/聚集体。这些结果表明，线粒体外膜的mtMGST1被GA通过硫醇氧化激活，导致蛋白质寡聚/聚集，这可能有助于形成ros介导的、csa不敏感的MPT孔，提示mtMGST1调节MPT的新机制。(C) 2008爱思唯尔公司版权所有。
We recently reported that the glutathione transferase in rat liver mitochondrial membranes (mtMGST1) is activated by S-glutathionylation and the activated mtMGST1 contributes to the mitochondrial permeability transition (MPT) pore and cytochrome c release from mitochondria [Lee, K.K., Shimoji, M., Quazi, S.H., Sunakawa, H., Aniya, Y., 2008. Novel function of glutathione transferase in rat liver mitochondrial membrane: role for cytochrome c release from mitochondria. Toxcol. Appl. Pharmacol. 232. 109-118]. In the present study we investigated the effect of reactive oxygen species (ROS), generator gallic acid (GA) and GST inhibitors on mtMGST1 and the MITE When rat liver mitochondria were incubated with GA, mtMGSTI activity was increased to about 3 fold and the increase was inhibited with antioxidant enzymes and singlet oxygen quenchers including 1,4-diazabicyclo [2,2,2] octane (DABCO). GA-mediated mtMGST1 activation was prevented by GST inhibitors such as tannic acid, hematin, and cibacron blue and also by cyclosporin A (CsA). In addition, GA induced the mitochondrial swelling which was also inhibited by GST inhibitors, but not by MPT inhibitors CsA. ADP, and bongkrekic acid. GA also released cytochrome c from the mitochondria which was inhibited completely by DABCO, moderately by GST inhibitors, and somewhat by CsA. Ca2+-mediated mitochondrial swelling and cytochrome c release were inhibited by MPT inhibitors but not by GST inhibitors. When the outer mitochondrial membrane was isolated after treatment of mitochondria with GA, mtMGST1 activity was markedly increased and oligomer/aggregate of mtMGST1 was observed. These results indicate that mtMGST1 in the outer mitochondrial membrane is activated by GA through thiol oxidation leading to protein oligomerization/aggregation, which may contribute to the formation of ROS-mediated, CsA-insensitive MPT pore, suggesting a novel mechanism for regulation of the MPT by mtMGST1. (C) 2008 Elsevier Inc. All rights reserved.