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.
Maria Elisabetta ClementiMichela PizzoferratoGiada BianchettiAnna BrancatoBeatrice SampaoleseGiuseppe MaulucciGiuseppe TringaliPublished in: Biomedicines (2022)
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 H 2 O 2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H 2 O 2 -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 (ΔΨ m ) 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.
Keyphrases
- oxidative stress
- induced apoptosis
- dna damage
- diabetic rats
- ischemia reperfusion injury
- hydrogen peroxide
- signaling pathway
- endothelial cells
- clinical trial
- cell death
- emergency department
- endoplasmic reticulum stress
- randomized controlled trial
- nitric oxide
- reactive oxygen species
- heat shock
- epithelial mesenchymal transition
- physical activity
- weight gain
- climate change
- pi k akt
- atomic force microscopy
- binding protein
- high resolution
- amino acid
- combination therapy
- replacement therapy