Drp1介导的线粒体分裂与NADPH氧化酶在视网膜蓝光损伤中的作用机制研究

LED光源广泛使用正引发蓝光视觉危害问题。活性氧ROS是视网膜蓝光损伤的关键因子，但ROS主要来源线粒体和NADPH氧化酶如何协调参与视网膜蓝光损伤机制尚不明。本课题前期研究（Front Mol Neurosci，2018 Nov）发现：蓝光可诱导线粒体分裂蛋白Drp1和NADPH氧化酶NOX4表达、IκBα磷酸化、ROS产生和视网膜节细胞凋亡；抑制或敲低Drp1能减弱蓝光诱导的IκBα磷酸化、NOX4表达、ROS产生和凋亡；NF-κB抑制剂也可抑制蓝光诱导NOX4表达。综上所述，我们推测：Drp1介导的线粒体分裂可能经NF-κB上调NOX4表达，并协同产生大量ROS参与视网膜蓝光损伤。为验证该假说，将深入探讨Drp1介导的线粒体分裂在ROS产生、NF-κB激活和NOX4表达中的作用机制，及Drp1和NOX4抑制剂对视网膜蓝光损伤的疗效。故本课题将为更好地防治视网膜蓝光损伤寻找药物新靶点。

The widespread use of LED lighting products causes blue light hazard, especially the retinal blue light hazard. It has been recognized that reactive oxygen species (ROS) play a crucial role in blue light-induced retinal injury. However, the mechanism how the two main ROS sources, mitochondria and NADPH oxidases (NOX) are synergistically involved in blue light-induced retinal injury remains to be elucidated. In the preliminary experiments, we found that blue light irradiation up-regulated expression of mitochondrial fission protein Drp1 and NADPH oxidase NOX4, IκBα S36 phosphorylation, and stimulated mitochondrial fission, ROS production and apoptosis. Inhibition of Drp1 by Mdivi-1 or knockdown of Drp1 efficiently attenuated blue light-induced NOX4 expression, IκBα S36 phosphorylation, mitochondrial fission, ROS production and apoptosis. Moreover, NF-κB inhibitor PDTC also alleviated blue light-induced NOX4 expression in R28 cells. These preliminary data are recently published in Front Mol Neurosci. 2018 Nov; 11:432. doi: 10.3389/fnmol.2018.00432. Based on our preliminary studies and the previous reports, we hypothesize that Drp1-mediated mitochondrial fission may up-regulate the expression of NOX4 via NF-κB signaling pathway, and induce blue light-induced retinal injuries through synergistic production of ROS. To prove our hypothesis, we will further investigate the underlying mechanism how Drp1-mediated mitochondrial fission regulates ROS production and NOX4 expression via NF-κB signaling pathway, and examine the therapeutic effect of Drp1 inhibitor or NADPH oxidase inhibitor on blue light-induced retinal injury. Therefore, this study will provide a potential therapeutic target for the retinal blue light hazard in the future.