Laboratory for Optic Nerve Biology, Hamilton Glaucoma Center and Department of Ophthalmology, University of California, San Diego, La Jolla, CA, USA.
Cell Death Dis. 2013 Oct 3;4(10):e820. doi: 10.1038/cddis.2013.341.
Oxidative stress contributes to dysfunction of glial cells in the optic nerve head (ONH). However, the biological basis of the precise functional role of mitochondria in this dysfunction is not fully understood. Coenzyme Q10 (CoQ10), an essential cofactor of the electron transport chain and a potent antioxidant, acts by scavenging reactive oxygen species (ROS) for protecting neuronal cells against oxidative stress in many neurodegenerative diseases. Here, we tested whether hydrogen peroxide (100 μM H2O2)-induced oxidative stress alters the mitochondrial network, oxidative phosphorylation (OXPHOS) complex (Cx) expression and bioenergetics, as well as whether CoQ10 can ameliorate oxidative stress-mediated alterations in mitochondria of the ONH astrocytes in vitro. Oxidative stress triggered the activation of ONH astrocytes and the upregulation of superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) protein expression in the ONH astrocytes. In contrast, CoQ10 not only prevented activation of ONH astrocytes but also significantly decreased SOD2 and HO-1 protein expression in the ONH astrocytes against oxidative stress. Further, CoQ10 prevented a significant loss of mitochondrial mass by increasing mitochondrial number and volume density and by preserving mitochondrial cristae structure, as well as promoted mitofilin and peroxisome-proliferator-activated receptor-γ coactivator-1 protein expression in the ONH astrocyte, suggesting an induction of mitochondrial biogenesis. Finally, oxidative stress triggered the upregulation of OXPHOS Cx protein expression, as well as reduction of cellular adeonsine triphosphate (ATP) production and increase of ROS generation in the ONH astocytes. However, CoQ10 preserved OXPHOS protein expression and cellular ATP production, as well as decreased ROS generation in the ONH astrocytes. On the basis of these observations, we suggest that oxidative stress-mediated mitochondrial dysfunction or alteration may be an important pathophysiological mechanism in the dysfunction of ONH astrocytes. CoQ10 may provide new therapeutic potentials and strategies for protecting ONH astrocytes against oxidative stress-mediated mitochondrial dysfunction or alteration in glaucoma and other optic neuropathies.
氧化应激导致视神经头（ONH）中的神经胶质细胞功能障碍。然而，线粒体在这种功能障碍中的精确功能作用的生物学基础尚未完全理解。辅酶 Q10（CoQ10）是电子传递链的必需辅助因子，也是一种有效的抗氧化剂，可通过清除活性氧 (ROS) 来保护神经元细胞免受许多神经退行性疾病中的氧化应激。在这里，我们测试了过氧化氢 (100 μM H2O2) 诱导的氧化应激是否会改变线粒体网络、氧化磷酸化 (OXPHOS) 复合物 (Cx) 表达和生物能，以及 CoQ10 是否可以改善体外 ONH 星形胶质细胞中线粒体的氧化应激介导的改变。氧化应激引发了 ONH 星形胶质细胞的激活，并上调了 ONH 星形胶质细胞中超氧化物歧化酶 2 (SOD2) 和血红素加氧酶-1 (HO-1) 的蛋白表达。相比之下，CoQ10 不仅防止了 ONH 星形胶质细胞的激活，而且在氧化应激下还显著降低了 ONH 星形胶质细胞中 SOD2 和 HO-1 的蛋白表达。此外，CoQ10 通过增加线粒体数量和体积密度以及维持线粒体嵴结构来防止线粒体质量的显著损失，同时还促进了 ONH 星形胶质细胞中的线粒体融合蛋白和过氧化物酶体增殖物激活受体-γ 共激活因子 1 蛋白的表达，表明诱导了线粒体生物发生。最后，氧化应激引发了 OXPHOS Cx 蛋白表达的上调，以及 ONH 星形胶质细胞中细胞三磷酸腺苷 (ATP) 产生的减少和 ROS 生成的增加。然而，CoQ10 保留了 OXPHOS 蛋白表达和细胞 ATP 产生，并减少了 ONH 星形胶质细胞中的 ROS 生成。基于这些观察结果，我们认为氧化应激介导的线粒体功能障碍或改变可能是 ONH 星形胶质细胞功能障碍的重要病理生理机制。CoQ10 可能为保护 ONH 星形胶质细胞免受氧化应激介导的线粒体功能障碍或改变提供新的治疗潜力和策略，用于青光眼和其他视神经病变。
