Department of Pharmaceutical Sciences, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Cells. 2022 Nov 24;11(23):3756. doi: 10.3390/cells11233756.
Müller glia (MG), the principal glial cell of the retina, have a metabolism that defies categorization into glycolytic versus oxidative. We showed that MG mount a strong hypoxia response to ocular hypertension, raising the question of their relative reliance on mitochondria for function. To explore the role of oxidative phosphorylation (OXPHOS) in MG energy production in vivo, we generated and characterized adult mice in which MG have impaired cytochrome c oxidase (COXIV) activity through knockout of the COXIV constituent COX10. Histochemistry and protein analysis showed that COXIV protein levels were significantly lower in knockout mouse retina compared to control. Loss of COXIV activity in MG did not induce structural abnormalities, though oxidative stress was increased. Electroretinography assessment showed that knocking out COX10 significantly impaired scotopic a- and b-wave responses. Inhibiting mitochondrial respiration in MG also altered the retinal glycolytic profile. However, blocking OXPHOS in MG did not significantly exacerbate retinal ganglion cell (RGC) loss or photopic negative response after ocular hypertension (OHT). These results suggest that MG were able to compensate for reduced COXIV stability by maintaining fundamental processes, but changes in retinal physiology and metabolism-associated proteins indicate subtle changes in MG function.
Müller 胶质细胞（MG）是视网膜的主要神经胶质细胞，其代谢方式难以归类为糖酵解与氧化。我们发现 MG 在眼高压下会产生强烈的缺氧反应，这引发了一个问题，即它们对线粒体功能的相对依赖程度。为了研究氧化磷酸化（OXPHOS）在体内 MG 能量产生中的作用，我们通过敲除 COX10 生成并表征了成年 COX10 敲除小鼠，从而导致 MG 中的细胞色素 c 氧化酶（COXIV）活性受损。组织化学和蛋白质分析表明，与对照组相比，COXIV 蛋白水平在敲除鼠视网膜中显著降低。MG 中 COXIV 活性的丧失并未诱导结构异常，尽管氧化应激增加。视网膜电图评估表明，敲除 COX10 显著损害了暗视 a 波和 b 波反应。抑制 MG 中的线粒体呼吸也改变了视网膜的糖酵解谱。然而，在眼高压（OHT）后，阻断 MG 中的 OXPHOS 并没有显著加重视网膜神经节细胞（RGC）的损失或光暗负反应。这些结果表明，MG 能够通过维持基本过程来补偿 COXIV 稳定性的降低，但视网膜生理学和代谢相关蛋白的变化表明 MG 功能存在细微变化。
