Mitochondrial Reactive Oxygen Species Regulate Transforming Growth Factor-β Signaling
Mitochondrial Reactive Oxygen Species Regulate Transforming Growth Factor-β Signaling
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DOI：
10.1074/jbc.m112.431973
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发表时间：
2013-01-11
影响因子：
4.8
通讯作者：
Chandel, Navdeep S.
中科院分区：
文献类型：
--
作者：
Jain, Manu;Rivera, Stephanie;Chandel, Navdeep S.
TGF-β信号传导是正常组织修复所需的;然而，过度的TGF-β信号传导可导致成纤维细胞中强的促纤维化基因表达，从而导致组织纤维化。TGF-β与细胞表面受体结合，导致Smad家族转录因子磷酸化以启动基因表达。TGF-β还启动Smad非依赖性途径，其增强基因表达。在这里，我们报告说，线粒体活性氧（ROS）产生的复合物III所需的TGF-β诱导的原代正常人肺成纤维细胞的基因表达。TGF-β诱导的ROS可在线粒体基质和细胞质中检测到。线粒体靶向抗氧化剂显著减弱TGF-β诱导的基因表达，而不影响Smad磷酸化或核转位。遗传性破坏线粒体复合物III产生的ROS产生减弱TGF-β诱导的促纤维化基因表达。此外，抑制线粒体ROS产生减弱了N 0X 4（NADPH氧化酶4）表达，这是TGF-β诱导的肌成纤维细胞分化所需的。肺纤维化患者的肺成纤维细胞比正常人肺成纤维细胞产生更多的线粒体ROS，并且血管靶向抗氧化剂减弱了正常和纤维化肺成纤维细胞中的促纤维化基因表达。总的来说，我们的研究结果表明，线粒体ROS是正常的TGF-β介导的基因表达所必需的，靶向线粒体ROS可能是有益的与过度纤维化相关的疾病。
TGF-beta signaling is required for normal tissue repair; however, excessive TGF-beta signaling can lead to robust profibrotic gene expression in fibroblasts, resulting in tissue fibrosis. TGF-beta binds to cell-surface receptors, resulting in the phosphorylation of the Smad family of transcription factors to initiate gene expression. TGF-beta also initiates Smad-independent pathways, which augment gene expression. Here, we report that mitochondrial reactive oxygen species (ROS) generated at complex III are required for TGF-beta-induced gene expression in primary normal human lung fibroblasts. TGF-beta-induced ROS could be detected in both the mitochondrial matrix and cytosol. Mitochondrially targeted antioxidants markedly attenuated TGF-beta-induced gene expression without affecting Smad phosphorylation or nuclear translocation. Genetically disrupting mitochondrial complex III-generated ROS production attenuated TGF-beta-induced profibrotic gene expression. Furthermore, inhibiting mitochondrial ROS generation attenuated NOX4 (NADPH oxidase 4) expression, which is required for TGF-beta induced myofibroblast differentiation. Lung fibroblasts from patients with pulmonary fibrosis generated more mitochondrial ROS than normal human lung fibroblasts, and mitochondrially targeted antioxidants attenuated profibrotic gene expression in both normal and fibrotic lung fibroblasts. Collectively, our results indicate that mitochondrial ROS are essential for normal TGF-beta-mediated gene expression and that targeting mitochondrial ROS might be beneficial in diseases associated with excessive fibrosis.