Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation
Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation
复制标题
DOI：
10.1074/jbc.m111.223602
复制
发表时间：
2011-05-06
影响因子：
4.8
通讯作者：
LoGrasso, Philip V.
中科院分区：
文献类型：
--
作者：
Chambers, Jeremy W.;LoGrasso, Philip V.
JNK信号级联对于细胞对各种环境和细胞刺激的反应至关重要。虽然JNK信号转导的基因表达方面得到了很好的研究，但关于JNK信号转导的生理影响的数据很少。为了弥合这一差距，我们研究了JNK如何影响HeLa细胞的生理学。我们观察到，JNK活性的抑制和JNK沉默与siRNA降低了活性氧（ROS）的水平在茴香霉素诱导的压力在HeLa细胞中产生。沉默p38对茴香霉素胁迫下ROS的产生没有显著影响。此外，JNK信号介导的放大的ROS生产过程中的压力。线粒体超氧化物的产生被证明是JNK诱导的ROS扩增的来源，因为NADPH氧化酶抑制剂对JNK介导的ROS产生几乎没有影响。使用从JNK无效成纤维细胞中分离的线粒体并靶向JNK的线粒体支架，Sab，我们证明了线粒体JNK信号传导负责线粒体超氧化物扩增。这些结果表明，细胞应激改变了线粒体，导致JNK易位到线粒体，并扩增了主要由复合物I产生的ROS的80%。这项工作表明，JNK线粒体信号传导存在一系列事件，ROS激活JNK，从而影响线粒体生理学，这可能对细胞存活和死亡产生影响。
The JNK signaling cascade is critical for cellular responses to a variety of environmental and cellular stimuli. Although gene expression aspects of JNK signal transduction are well studied, there are minimal data on the physiological impact of JNK signaling. To bridge this gap, we investigated how JNK impacted physiology in HeLa cells. We observed that inhibition of JNK activity and JNK silencing with siRNA reduced the level of reactive oxygen species (ROS) generated during anisomycin-induced stress in HeLa cells. Silencing p38 had no significant impact on ROS generation under anisomycin stress. Moreover, JNK signaling mediated amplification of ROS production during stress. Mitochondrial superoxide production was shown to be the source of JNK-induced ROS amplification, as an NADPH oxidase inhibitor demonstrated little impact on JNK-mediated ROS generation. Using mitochondrial isolation from JNK null fibroblasts and targeting the mitochondrial scaffold of JNK, Sab, we demonstrated that mitochondrial JNK signaling was responsible for mitochondrial superoxide amplification. These results suggest that cellular stress altered mitochondria, causing JNK to translocate to the mitochondria and amplify up to 80% of the ROS generated largely by Complex I. This work demonstrates that a sequence of events exist for JNK mitochondrial signaling whereby ROS activates JNK, thereby affecting mitochondrial physiology, which can have effects on cell survival and death.