Mitochondrial reactive oxygen species trigger hypoxia-induced transcription
Mitochondrial reactive oxygen species trigger hypoxia-induced transcription
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DOI：
10.1073/pnas.95.20.11715
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发表时间：
1998-09-29
影响因子：
11.1
通讯作者：
Schumacker, PT
中科院分区：
文献类型：
--
作者：
Chandel, NS;Maltepe, E;Schumacker, PT
促红细胞生成素、糖酵解酶和血管内皮生长因子在低氧或氯化钴(CoCl2)作用下被转录激活。然而，无论是细胞臭氧感知的机制还是钴的机制都还不完全清楚。我们测试了线粒体在低氧过程中是否作为Oz感受器，以及低氧和钴是否通过增加活性氧物种(ROS)的生成来激活转录。结果表明：(1)野生型Hep3B细胞在低氧(1.5%O~(-2))或CoCl2孵育时ROS生成增加；(Ii)线粒体DNA耗竭的Hep3B细胞(Rho(0)细胞)在低氧条件下不能呼吸，不能激活促红细胞生成素、糖酵解酶或血管内皮生长因子的mRNA，也不能在低氧条件下增加ROS生成；(Iii)Rho(0)细胞响应CoCl2而增加ROS生成并保持诱导这些基因表达的能力；以及(Iv)抗氧化剂吡咯烷二硫代氨基甲酸酯和ebselen在野生型细胞中取消了这些基因在缺氧或CoCl2中的转录激活，并在Rho(O)细胞中取消了对CoCl2的反应。因此，低氧通过线粒体依赖的信号过程激活转录，涉及增加的ROS，而CoCl2通过线粒体非依赖机制刺激ROS的产生来激活转录。
Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl2) in Hep3B cells. However, neither the mechanism of cellular Oz sensing nor that of cobalt is fully understood. We tested whether mitochondria act as Oz sensors during hypoxia and whether hypoxia and cobalt activate transcription by increasing generation of reactive oxygen species (ROS). Results show (i) wild-type Hep3B cells increase ROS generation during hypoxia (1.5% O-2) or CoCl2 incubation, (ii) Hep3B cells depleted of mitochondrial DNA (rho(0) cells) fail to respire, fail to activate mRNA for erythropoietin, glycolytic enzymes, or vascular endothelial growth factor during hypoxia, and fail to increase ROS generation during hypoxia; (iii) rho(0) cells increase ROS generation in response to CoCl2 and retain the ability to induce expression of these genes; and (iv) the antioxidants pyrrolidine dithiocarbamate and ebselen abolish transcriptional activation of these genes during hypoxia or CoCl2 in wild-type cells, and abolish the response to CoCl2 in rho(o) cells. Thus, hypoxia activates transcription via a mitochondria-dependent signaling process involving increased ROS, whereas CoCl2 activates transcription by stimulating ROS generation via a mitochondria-independent mechanism.