Shyam Rajalekshmy, Ogando Diego G, Bonanno Joseph A
Vision Science Program, School of Optometry, Indiana University, Bloomington, IN, United States.
Front Cell Dev Biol. 2022 Apr 26;10:878395. doi: 10.3389/fcell.2022.878395. eCollection 2022.
Recent studies from mice have identified glutamine-induced mitochondrial dysfunction as a significant contributor toward oxidative stress, impaired lysosomal function, aberrant autophagy, and cell death in this Congenital Hereditary Endothelial Dystrophy (CHED) model. Because lysosomes are derived from endoplasmic reticulum (ER)-Golgi, we asked whether ER function is affected by mitochondrial ROS in KO corneal endothelial cells. In mouse corneal endothelial tissue, we observed the presence of dilated ER and elevated expression of ER stress markers BIP and CHOP. KO mouse corneal endothelial cells incubated with glutamine showed increased aggresome formation, BIP and GADD153, as well as reduced ER Ca release as compared to WT. Induction of mitoROS by ETC inhibition also led to ER stress in WT cells. Treatment with the mitochondrial ROS quencher MitoQ, restored ER Ca release and relieved ER stress markers in KO cells . Systemic MitoQ also reduced BIP expression in KO endothelium. We conclude that mitochondrial ROS can induce ER stress in corneal endothelial cells.
最近对小鼠的研究已经确定，在这种先天性遗传性内皮营养不良（CHED）模型中，谷氨酰胺诱导的线粒体功能障碍是导致氧化应激、溶酶体功能受损、自噬异常和细胞死亡的一个重要因素。由于溶酶体来源于内质网（ER）-高尔基体，我们不禁要问，在敲除（KO）角膜内皮细胞中，ER功能是否受到线粒体活性氧（ROS）的影响。在小鼠角膜内皮组织中，我们观察到内质网扩张以及内质网应激标志物BIP和CHOP的表达升高。与野生型（WT）相比，用谷氨酰胺孵育的敲除小鼠角膜内皮细胞显示出聚集体形成增加、BIP和GADD153升高，以及内质网钙释放减少。通过电子传递链（ETC）抑制诱导线粒体ROS也会导致野生型细胞出现内质网应激。用线粒体ROS淬灭剂MitoQ处理可恢复敲除细胞中的内质网钙释放并减轻内质网应激标志物。全身性给予MitoQ也可降低敲除小鼠内皮中的BIP表达。我们得出结论，线粒体ROS可诱导角膜内皮细胞中的内质网应激。
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