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Inhibition of oxidative stress by coenzyme Q10 increases mitochondrial mass and improves bioenergetic function in optic nerve head astrocytes.

Noh YH, Kim KY, Shim MS, Choi SH, Choi S, Ellisman MH, Weinreb RN, Perkins GA, Ju WK - Cell Death Dis (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Optic Nerve Biology, Hamilton Glaucoma Center and Department of Ophthalmology, University of California, San Diego, La Jolla, CA, USA.

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.

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3D reconstruction of mitochondrial cristae in the ONH astrocytes. Oxidative stress dilated cristae that were prevented by CoQ10/H2O2 treatment. Electron tomography generated high-resolution, 3D reconstructions of control, H2O2-exposed and CoQ10/H2O2-treated mitochondria. Slices (1.4-nm thick) through the middle of electron microscopy tomographic volumes of mitochondria are shown on the left. Surface-rendered volumes of the segmented mitochondria provide information concerning shape and cristae architecture. The outer mitochondrial membrane is shown in blue (made translucent to better visualize the cristae) and cristae are in various colors. The long control mitochondrion has 46 cristae, the H2O2-exposed has 47 cristae distributed in the four mitochondria that are lined up and the CoQ10/H2O2-treated mitochondrion has 27 cristae. The mean of cristae widths is 50% greater in the H2O2-exposed mitochondria compared with the control and CoQ10 pretreatment samples. Scale bar, 250 nm (all panels). Values are mean ±S.E.M. *Significant at P<0.05 and ***Significant at P<0.001 compared with vehicle-treated control ONH astrocytes or H2O2-treated ONH astrocytes. Representative graphs show the measurement of cristae widths and abundance in the mitochondria. CoQ10, coenzyme Q10; H2O2, hydrogen peroxide
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fig5: 3D reconstruction of mitochondrial cristae in the ONH astrocytes. Oxidative stress dilated cristae that were prevented by CoQ10/H2O2 treatment. Electron tomography generated high-resolution, 3D reconstructions of control, H2O2-exposed and CoQ10/H2O2-treated mitochondria. Slices (1.4-nm thick) through the middle of electron microscopy tomographic volumes of mitochondria are shown on the left. Surface-rendered volumes of the segmented mitochondria provide information concerning shape and cristae architecture. The outer mitochondrial membrane is shown in blue (made translucent to better visualize the cristae) and cristae are in various colors. The long control mitochondrion has 46 cristae, the H2O2-exposed has 47 cristae distributed in the four mitochondria that are lined up and the CoQ10/H2O2-treated mitochondrion has 27 cristae. The mean of cristae widths is 50% greater in the H2O2-exposed mitochondria compared with the control and CoQ10 pretreatment samples. Scale bar, 250 nm (all panels). Values are mean ±S.E.M. *Significant at P<0.05 and ***Significant at P<0.001 compared with vehicle-treated control ONH astrocytes or H2O2-treated ONH astrocytes. Representative graphs show the measurement of cristae widths and abundance in the mitochondria. CoQ10, coenzyme Q10; H2O2, hydrogen peroxide

Mentions: To better visualize the cristae, we performed electron tomography, a technique that provides the highest resolution three-dimensional (3D) structure determination of mitochondria. We generated tomographic reconstructions of 15 control, 60 H2O2-exposed and 33 CoQ10/H2O2-treated mitochondria and noticed that the cristae appeared dilated in the H2O2-exposed mitochondria (Figure 5). Measurements of cristae widths in the mitochondrial volumes showed that control cristae were 32±5 nm (mean±S.D.) across (membranes included), CoQ10/H2O2-treated cristae were 31±6 nm across, yet H2O2-exposed cristae were 48±17 nm across, a value statistically different from control and CoQ10/H2O2-treatment values (P<0.001, Figure 5). The variation in cristae width was much greater in the H2O2-exposed mitochondria reflecting that not all the cristae were dilated. In comparison, the cristae widths in control and CoQ10/H2O2-treated mitochondria were more uniform (Figure 5). The abnormal cristae associated with oxidative stress are consistent with our finding of reduced ATP production. To further determine cristae abundance, we also performed measurment of mitochondrial cristae abundance. The parameter is cristae membrane surface area (SA) normalized to the outer membrane area, that is, cristae membrane SA divided by outer membrane SA that is dimensionless. Measurement of cristae abundance in the mitochondria showed that H2O2-exposed cristae significantly increased cristae abundance by 1.75±0.09 (n=5, mean±S.E.M.) compared with control cristae abundance by 0.95±0.26 (n=5; P<0.05, Figure 5). Pretreatment of CoQ10 decreased cristae abundance by 1.43±0.33 (n=5) in the ONH astrocytes exposed to H2O2; however, there was no statistical difference between H2O2 and CoQ10/H2O2-treated ONH astrocytes (Figure 5).


Inhibition of oxidative stress by coenzyme Q10 increases mitochondrial mass and improves bioenergetic function in optic nerve head astrocytes.

Noh YH, Kim KY, Shim MS, Choi SH, Choi S, Ellisman MH, Weinreb RN, Perkins GA, Ju WK - Cell Death Dis (2013)

3D reconstruction of mitochondrial cristae in the ONH astrocytes. Oxidative stress dilated cristae that were prevented by CoQ10/H2O2 treatment. Electron tomography generated high-resolution, 3D reconstructions of control, H2O2-exposed and CoQ10/H2O2-treated mitochondria. Slices (1.4-nm thick) through the middle of electron microscopy tomographic volumes of mitochondria are shown on the left. Surface-rendered volumes of the segmented mitochondria provide information concerning shape and cristae architecture. The outer mitochondrial membrane is shown in blue (made translucent to better visualize the cristae) and cristae are in various colors. The long control mitochondrion has 46 cristae, the H2O2-exposed has 47 cristae distributed in the four mitochondria that are lined up and the CoQ10/H2O2-treated mitochondrion has 27 cristae. The mean of cristae widths is 50% greater in the H2O2-exposed mitochondria compared with the control and CoQ10 pretreatment samples. Scale bar, 250 nm (all panels). Values are mean ±S.E.M. *Significant at P<0.05 and ***Significant at P<0.001 compared with vehicle-treated control ONH astrocytes or H2O2-treated ONH astrocytes. Representative graphs show the measurement of cristae widths and abundance in the mitochondria. CoQ10, coenzyme Q10; H2O2, hydrogen peroxide
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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fig5: 3D reconstruction of mitochondrial cristae in the ONH astrocytes. Oxidative stress dilated cristae that were prevented by CoQ10/H2O2 treatment. Electron tomography generated high-resolution, 3D reconstructions of control, H2O2-exposed and CoQ10/H2O2-treated mitochondria. Slices (1.4-nm thick) through the middle of electron microscopy tomographic volumes of mitochondria are shown on the left. Surface-rendered volumes of the segmented mitochondria provide information concerning shape and cristae architecture. The outer mitochondrial membrane is shown in blue (made translucent to better visualize the cristae) and cristae are in various colors. The long control mitochondrion has 46 cristae, the H2O2-exposed has 47 cristae distributed in the four mitochondria that are lined up and the CoQ10/H2O2-treated mitochondrion has 27 cristae. The mean of cristae widths is 50% greater in the H2O2-exposed mitochondria compared with the control and CoQ10 pretreatment samples. Scale bar, 250 nm (all panels). Values are mean ±S.E.M. *Significant at P<0.05 and ***Significant at P<0.001 compared with vehicle-treated control ONH astrocytes or H2O2-treated ONH astrocytes. Representative graphs show the measurement of cristae widths and abundance in the mitochondria. CoQ10, coenzyme Q10; H2O2, hydrogen peroxide
Mentions: To better visualize the cristae, we performed electron tomography, a technique that provides the highest resolution three-dimensional (3D) structure determination of mitochondria. We generated tomographic reconstructions of 15 control, 60 H2O2-exposed and 33 CoQ10/H2O2-treated mitochondria and noticed that the cristae appeared dilated in the H2O2-exposed mitochondria (Figure 5). Measurements of cristae widths in the mitochondrial volumes showed that control cristae were 32±5 nm (mean±S.D.) across (membranes included), CoQ10/H2O2-treated cristae were 31±6 nm across, yet H2O2-exposed cristae were 48±17 nm across, a value statistically different from control and CoQ10/H2O2-treatment values (P<0.001, Figure 5). The variation in cristae width was much greater in the H2O2-exposed mitochondria reflecting that not all the cristae were dilated. In comparison, the cristae widths in control and CoQ10/H2O2-treated mitochondria were more uniform (Figure 5). The abnormal cristae associated with oxidative stress are consistent with our finding of reduced ATP production. To further determine cristae abundance, we also performed measurment of mitochondrial cristae abundance. The parameter is cristae membrane surface area (SA) normalized to the outer membrane area, that is, cristae membrane SA divided by outer membrane SA that is dimensionless. Measurement of cristae abundance in the mitochondria showed that H2O2-exposed cristae significantly increased cristae abundance by 1.75±0.09 (n=5, mean±S.E.M.) compared with control cristae abundance by 0.95±0.26 (n=5; P<0.05, Figure 5). Pretreatment of CoQ10 decreased cristae abundance by 1.43±0.33 (n=5) in the ONH astrocytes exposed to H2O2; however, there was no statistical difference between H2O2 and CoQ10/H2O2-treated ONH astrocytes (Figure 5).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Optic Nerve Biology, Hamilton Glaucoma Center and Department of Ophthalmology, University of California, San Diego, La Jolla, CA, USA.

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.

Show MeSH
Related in: MedlinePlus