Cytoprotective Effect of Idebenone through Modulation of the Intrinsic Mitochondrial Pathway of Apoptosis in Human Retinal Pigment Epithelial Cells Exposed to Oxidative Stress Induced by Hydrogen Peroxide

Abstract

Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber’s hereditary optic neuropathy. Mitochondria of retinal pigment epithelium (RPE) are particularly vulnerable to oxidative damage associated with cellular senescence. Therefore, the aim of this study was to explore idebenone’s cytoprotective effect and its underlying mechanism. We used a human-RPE cell line (ARPE-19) exposed to idebenone pre-treatment for 24 h followed by conditions inducing H2O2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H2O2-lowered cell viability in the RPE culture; (b) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation; (c) increased Bcl-2 protein levels, leaving unmodified those of Bax, thereby reducing the Bax/Bcl-2 ratio; (d) maintained the mitochondrial membrane potential (ΔΨm) at physiological levels, preserving the functionality of mitochondrial respiratory complexes and counteracting the excessive production of ROS; and (e) reduced mitochondrial cytochrome C-mediated caspase-3 activity. Taken together, our findings show that idebenone protects RPE from oxidative damage by modulating the intrinsic mitochondrial pathway of apoptosis, suggesting its possible role in retinal epitheliopathies associated with mitochondrial dysfunction.

Investigation of DHA-Induced Regulation of Redox Homeostasis in Retinal Pigment Epithelium Cells through the Combination of Metabolic Imaging and Molecular Biology

“…Figure 3 B shows that neither HG nor DHA under both physiological and HG conditions stimulate the activation of Nrf2 mRNA expression, with values 1.98 ± 1.18 for HG, 1.39 ± 0.72 for DHA, and 1.48 ± 0.71 for HG+DHA respectively. To evaluate the potential transcriptional activation of Nrf2, we both assayed Nrf2 protein expression in whole cells subjected to the different treatments (see Figure S2, Supplementary Materials ) [ 40 ] and evaluated the expression of Nqo1 and HO-1. The normalized expression of HO-1 and NQO1 is reported in Figure 3 C,D, respectively.…”

Fisetin Attenuated Oxidative Stress-Induced Cellular Damage in ARPE-19 Human Retinal Pigment Epithelial Cells Through Nrf2-Mediated Activation of Heme Oxygenase-1

“…Recently, oxidative stress has been suggested as a critical factor in the pathogenesis of various retinal degenerative diseases ( Chan et al, 2020 ; Dammak et al, 2021 ; Clementi et al, 2022 ). Therefore, the application of antioxidants to preserve RPE functional integrity from oxidative damage can be considered as one of the prospective approaches to reduce the pathogenesis of ocular diseases including retinal degeneration ( Léveillard et al, 2019 ; Sadda et al, 2020 ).…”

Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications

“…Idebenone, a ubiquinone short-chain synthetic analog, is believed to restore mitochondrial ATP synthesis with antioxidant properties [ 241 ]. Punicalagin (2,3-hexahydroxydiphenoyl-gallagyl-D-glucose), a polyphenol extracted from pomegranate (Punica granatum), is a potent antioxidant in several cell types [ 242 ].…”

“…Previous studies showed that both idebenone and punicalagin could protected RPE from oxidative damage, suggesting their possible roles in DR and DME treatment. Idebenone protected RPE through modulation of the intrinsic mitochondrial pathway of apoptosis [ 241 ]. Punicalagin exerted its effect to reduce oxidative stress and decrease the apoptosis via enhancing mitochondrial functions [ 242 ].…”