Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production
Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production
复制标题
DOI：
10.1074/jbc.m210432200
复制
发表时间：
2003-03-07
影响因子：
4.8
通讯作者：
Robinson, JP
中科院分区：
文献类型：
--
作者：
Li, NY;Ragheb, K;Robinson, JP
鱼藤酮抑制线粒体呼吸链复合体I可诱导多种细胞死亡。然而，其机制仍然难以捉摸。由于活性氧（ROS）在细胞凋亡中起重要作用，而鱼藤酮抑制线粒体呼吸链复合体I被认为能够提高线粒体ROS的产生，我们研究了鱼藤酮诱导的细胞凋亡与线粒体活性氧之间的关系。鱼藤酮能够在HL-60细胞的分离线粒体和培养细胞中诱导线粒体复合体I底物支持的线粒体ROS产生。通过DNA断裂、细胞色素c释放和caspase 3活性证实鱼藤酮诱导的细胞凋亡。鱼藤酮诱导的细胞凋亡与鱼藤酮诱导的线粒体ROS产生之间存在定量相关性。抗氧化剂（谷胱甘肽、n -乙酰半胱氨酸和维生素q）可抑制鱼藤酮诱导的细胞凋亡。过表达镁超氧化物歧化酶的HT1080细胞对鱼藤酮诱导的细胞凋亡的抵抗能力强于对照细胞，也证实了鱼藤酮诱导的线粒体ROS在细胞凋亡中的作用。这些结果表明鱼藤酮能够通过增加线粒体活性氧的产生量来诱导细胞凋亡。
Inhibition of mitochondrial respiratory chain complex I by rotenone had been found to induce cell death in a variety of cells. However, the mechanism is still elusive. Because reactive oxygen species (ROS) play an important role in apoptosis and inhibition of mitochondrial respiratory chain complex I by rotenone was thought to be able to elevate mitochondrial ROS production, we investigated the relationship between rotenone-induced apoptosis and mitochondrial reactive oxygen species. Rotenone was able to induce mitochondrial complex I substrate-supported mitochondrial ROS production both in isolated mitochondria from HL-60 cells as well as in cultured cells. Rotenone-induced apoptosis was confirmed by DNA fragmentation, cytochrome c release, and caspase 3 activity. A quantitative correlation between rotenone-induced apoptosis and rotenone-induced mitochondrial ROS production was identified. Rotenone-induced apoptosis was inhibited by treatment with antioxidants (glutathione, N-acetylcysteine, and vitamin Q. The role of rotenone-induced mitochondrial ROS in apoptosis was also confirmed by the finding that HT1080 cells overexpressing magnesium superoxide dismutase were more resistant to rotenone-induced apoptosis than control cells. These results suggest that rotenone is able to induce apoptosis via enhancing the amount of mitochondrial reactive oxygen species production.