Abstract
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.
Highlights
Generates excessive reactive oxygen species (ROS), leading to mitochondrial damage, oxidative stress and apoptotic cell death.[1,2] Increasing evidence demonstrates that oxidative stress links to mitochondrial dysfunction in glaucomatous neurodegeneration.[2,3,4,5] A recent study reported that lamina cribrosa cells in the optic nerve head (ONH) from glaucomatous human patients showed increased ROS production, impaired mitochondrial function and elevated cytosolic Ca2 þ,3 suggesting that a cycle of oxidative stress, mitochondrial dysfunction and dysregulation of calcium homeostasis may contribute to the pathogenesis of ONH degeneration in glaucoma.[3]
Since the first evidence of impaired mitochondrial respiration-mediated mitochondrial dysfunction in patients with primary open-angle glaucoma,[4] we have found that mitochondrial dysfunction is associated with ONH degeneration and retinal ganglion cell (RGC) death in a mouse model of glaucoma,[11,12,13] suggesting a distinct mitochondrial dysfunction-mediated degenerative pathway in glaucomatous neurodegeneration
Pure ONH astrocytes were generated from postnatal day 5 Sprague–Dawley rats using a modification of a previous protocol by Hernandez et al.[23]
Summary
Generates excessive reactive oxygen species (ROS), leading to mitochondrial damage, oxidative stress and apoptotic cell death.[1,2] Increasing evidence demonstrates that oxidative stress links to mitochondrial dysfunction in glaucomatous neurodegeneration.[2,3,4,5] A recent study reported that lamina cribrosa cells in the optic nerve head (ONH) from glaucomatous human patients showed increased ROS production, impaired mitochondrial function and elevated cytosolic Ca2 þ ,3 suggesting that a cycle of oxidative stress, mitochondrial dysfunction and dysregulation of calcium homeostasis may contribute to the pathogenesis of ONH degeneration in glaucoma.[3] alteration of antioxidant enzymes has been implicated in glaucomatous ONH astrocytes,[6] it remains unknown whether oxidative stress alters the mitochondrial network and triggers bioenergetic dysfunction in the ONH astrocytes. Previous studies demonstrated that CoQ10 protects retinal cells against oxidative stress in vitro and in vivo, as well as prevents retinal damage induced by acute IOP elevation or excitotoxicity in vivo.[19,20,21,22]
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