A possible cooperation of SOD1 and cytochrome c in mitochondria-dependent apoptosis
A possible cooperation of SOD1 and cytochrome c in mitochondria-dependent apoptosis
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DOI：
10.1016/j.freeradbiomed.2005.09.037
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发表时间：
2006-01-01
影响因子：
7.4
通讯作者：
Inoue, M
中科院分区：
文献类型：
--
作者：
Li, Q;Sato, EF;Inoue, M
即使在生理条件下，有氧呼吸也会产生少量的活性氧（ROS）。由于已知ROS具有各种恶化作用，细胞逃避线粒体内和周围ROS影响的方式将决定细胞的命运。我们以前报道，铜，锌-超氧化物歧化酶（SOD 1），细胞溶质酶，也定位于线粒体在各种类型的细胞。因此，我们进行了这项研究，以阐明SOD 1定位在线粒体及其周围的生理意义。我们分析了各种试剂的影响，可以调节线粒体呼吸，活性氧代谢，亚细胞定位的SOD 1和细胞色素c。使用大鼠肝线粒体，我们已经表明，Ca 2+，Fe 2+，或长链脂肪酸增加了线粒体产生的ROS和由此产生的ROS氧化腺嘌呤核苷酸移位酶（ANT）中的关键巯基。ANT的氧化诱导线粒体肿胀，随后释放SOD 1和细胞色素c。虽然电子传递抑制剂，如鱼藤酮，抗霉素A，和KCN，也增加了ROS的产生，他们未能（i）氧化ANT中的关键巯基，（ii）诱导肿胀，（iii）释放SOD 1和细胞色素c。这些结果表明，ANT硫醇的氧化和膜渗透性转换孔的开放诱导SOD 1和细胞色素c的释放。我们证明，SOD 1的损失增加了线粒体对氧化应激的敏感性，同时释放SOD 1增强了由释放的细胞色素c引发的凋亡反应的恶性循环。因此，SOD 1在保护线粒体免受ROS诱导的损伤中具有重要作用。我们的数据还表明，SOD 1的释放平行细胞色素c的释放在所有条件下。我们认为，膜内定位的SOD 1是第三种试剂（沿着AIF），将调节细胞凋亡。(c)2005年爱思唯尔公司All rights reserved.
A small amount of reactive oxygen species (ROS) is generated through aerobic respiration even under physiological conditions. Because ROS are known to have various deteriorating actions, the way cells could evade the effects of ROS in and around mitochondria would determine the fate of cells. We previously reported that Cu,Zn -superoxide dismutase (SOD1), a cytosolic enzyme, is also localized in mitochondria in various types of cells. Therefore, we undertook this study to elucidate the physiological significance of SOD1 localization in and around mitochondria. We analyzed the effects of various reagents that could modulate mitochondrial respiration, ROS metabolism, and subcellular localization of SOD1 and cytochrome c. Using rat liver mitochondria, we have shown that Ca2+, Fe2+, or long-chain fatty acids increased the mitochondrial generation of ROS and that the resulting ROS oxidized the critical thiol groups in adenine nucleotide translocase (ANT). The oxidation of ANT induced mitochondrial swelling followed by the release of SOD1 and cytochrome c. Although inhibitors of electron transport, such as rotenone, antimycin A, and KCN, also increased ROS generation, they failed to (i) oxidize the critical thiol groups in ANT, (ii) induce swelling, and (iii) release SOD1 and cytochrome c. These results suggest that the oxidation of ANT thiols and the opening of the membrane permeability transition pores induce the release of both SOD1 and cytochrome c. We demonstrated that the loss of SOD1 increases the susceptibility of mitochondria to oxidative stresses and that the simultaneous release of SOD1 enhances the vicious cycle of apoptotic reactions triggered by the released cytochrome c. Therefore, SOD1 must have important roles in protecting mitochondria from ROS-induced injury. Our data also suggest that SOD1 release parallels cytochrome c release under all conditions. We propose that intramembranously localized SOD1 is a third reagent (along with AIF) that will regulate apoptosis. (c) 2005 Elsevier Inc. All rights reserved.