Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon
Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon
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DOI：
10.1016/j.redox.2020.101606
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发表时间：
2020-09-01
期刊：
影响因子：
11.4
通讯作者：
Avadhani, Narayan G.
中科院分区：
文献类型：
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作者：
Chowdhury, Anindya Roy;Zielonka, Jacek;Avadhani, Narayan G.
线粒体电子传递链是活性氧（ROS）的主要来源，也是ROS的靶点，在稳定缺氧诱导因子（HIF）和诱导AMPK途径中具有隐含的作用。在这里，我们使用了不同剂量的两种药剂，线粒体-百草枯和线粒体-二甲双胍，这两种药剂已经与阳离子三苯基膦（TPP+）部分缀合，以选择性地将它们靶向线粒体基质隔室，从而导致线粒体内ROS的位点特异性产生。这些试剂主要通过作用于复合物I诱导超氧化物（O-2（中心点-））产生。在Raw 264.7巨噬细胞、C2 C12骨骼肌细胞和HCT 116腺癌细胞中，我们发现靶向氧化剂可诱导ROS（O（2）（中心点-）和H2 O2）。在测试的所有三种细胞系中，靶向药物破坏了膜电位并激活了钙调神经磷酸酶和Cn依赖性逆行信号通路。低氧培养条件也诱导Cn激活和HIF 1 α激活的时间调节的方式，前者出现在较短的曝光时间。总之，我们的研究结果表明，线粒体氧化剂诱导的逆行信号是由膜电位的破坏和激活的Ca 2 +/Cn途径，是独立的ROS诱导的HIF 1 α或AMPK途径。
The mitochondrial electron transport chain is a major source of reactive oxygen species (ROS) and is also a target of ROS, with an implied role in the stabilization of hypoxia-inducible factor (HIF) and induction of the AMPK pathway. Here we used varying doses of two agents, Mito-Paraquat and Mito-Metformin, that have been conjugated to cationic triphenylphosphonium (TPP+) moiety to selectively target them to the mitochondrial matrix compartment, thereby resulting in the site-specific generation of ROS within mitochondria. These agents primarily induce superoxide (O-2(center dot-)) production by acting on complex I. In Raw264.7 macrophages, C2C12 skeletal myocytes, and HCT116 adenocarcinoma cells, we show that mitochondria-targeted oxidants can induce ROS (O(2)(center dot-)and H2O2). In all three cell lines tested, the mitochondria-targeted agents disrupted membrane potential and activated calcineurin and the Cn-dependent retrograde signaling pathway. Hypoxic culture conditions also induced Cn activation and HIF1 alpha activation in a temporally regulated manner, with the former appearing at shorter exposure times. Together, our results indicate that mitochondrial oxidant-induced retrograde signaling is driven by disruption of membrane potential and activation of Ca2+/Cn pathway and is independent of ROS-induced HIF1 alpha or AMPK pathways.