Department of Foundational Sciences at Central Michigan University College of Medicine, Mount Pleasant, MI, United States.
Department of Foundational Sciences at Central Michigan University College of Medicine, Mount Pleasant, MI, United States.
Redox Biol. 2019 Jan;20:107-117. doi: 10.1016/j.redox.2018.09.023. Epub 2018 Sep 29.
Dysfunction in mitochondrial oxidative phosphorylation (OXPHOS) underlies a wide spectrum of human ailments known as mitochondrial diseases. Deficiencies in complex I of the electron transport chain (ETC) contribute to 30-40% of all cases of mitochondrial diseases, and leads to eye disease including optic nerve atrophy and retinal degeneration. The mechanisms responsible for organ damage in mitochondrial defects may include energy deficit, oxidative stress, and an increase in the NADH/NAD redox ratio due to decreased NAD regeneration. Currently, there is no effective treatment to alleviate human disease induced by complex I defect. Photoreceptor cells have the highest energy demand and dependence on OXPHOS for survival, and the lowest reserve capacity indicating that they are sensitive to OXPHOS defects. We investigated the effect of mitochondrial OXPHOS deficiency on retinal photoreceptors in a model of mitochondrial complex I defect (apoptosis inducing factor, AIF-deficient mice, Harlequin mice), and tested the protective effect of a mitochondrial redox compound (methylene blue, MB) on mitochondrial and photoreceptor integrity. MB prevented the reduction in the retinal thickness and protein markers for photoreceptor outer segments, Muller and ganglion cells, and altered mitochondrial integrity and function induced by AIF deficiency. In rotenone-induced complex I deficient 661 W cells (an immortalized mouse photoreceptor cell line) MB decreased the NADH/NAD ratio and oxidative stress without correcting the energy deficit, and improved cell survival. MB deactivated the mitochondrial stress response pathways, the unfolding protein response and mitophagy. In conclusion, preserving mitochondrial structure and function alleviates retinal photoreceptor degeneration in mitochondrial complex I defect.
线粒体氧化磷酸化（OXPHOS）功能障碍是一系列被称为线粒体疾病的人类疾病的基础。电子传递链（ETC）复合物 I 的缺乏占所有线粒体疾病的 30-40%，并导致眼部疾病，包括视神经萎缩和视网膜变性。导致线粒体缺陷导致器官损伤的机制可能包括能量不足、氧化应激以及由于 NAD 再生减少导致的 NADH/NAD 氧化还原比增加。目前，尚无有效的治疗方法来缓解由复合物 I 缺陷引起的人类疾病。光感受器细胞的能量需求最高，对 OXPHOS 的依赖性最强，生存能力最低，储备能力最低，表明它们对 OXPHOS 缺陷敏感。我们研究了线粒体 OXPHOS 缺陷对线粒体复合物 I 缺陷模型（凋亡诱导因子，AIF 缺陷小鼠，小丑猫小鼠）中视网膜光感受器的影响，并测试了线粒体氧化还原化合物（亚甲蓝，MB）对线粒体和光感受器完整性的保护作用。MB 可防止 AIF 缺乏引起的视网膜厚度和光感受器外节、Muller 和节细胞的蛋白标志物减少，以及线粒体完整性和功能的改变。在鱼藤酮诱导的复合物 I 缺陷的 661W 细胞（一种永生化的小鼠光感受器细胞系）中，MB 降低了 NADH/NAD 比和氧化应激，而没有纠正能量不足，并提高了细胞存活率。MB 失活了线粒体应激反应途径、未折叠蛋白反应和线粒体自噬。总之，保持线粒体结构和功能可减轻线粒体复合物 I 缺陷引起的视网膜光感受器变性。
