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

Biomedicines

Anna Brancato¹  Giuseppe Maulucci²  Giada Bianchetti²  Maria Elisabetta Clementi³  Beatrice Sampaolese³  Giuseppe Tringali⁴  Michela Pizzoferrato⁴ 

[1] Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties of Excellence “G. D’Alessandro”, University of Palermo, 90127 Palermo, Italy;Fondazione Policlinico Universitario Agostino Gemelli IRCSS, 00168 Rome, Italy;Institute of Chemical Sciences and Technologies “Giulio Natta” (SCITEC)-CNR, Largo F. Vito 1, 00168 Rome, Italy;Pharmacology Section, Department of Health Care Surveillance and Bioethics, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy;

关键词: idebenone;    ARPE-19 (human-RPE cell line);    mitochondria;    oxidative stress;    nuclear factor erythroid 2-related factor (Nrf2);    apoptosis;   

DOI  :  10.3390/biomedicines10020503

来源: DOAJ

【 摘 要 】

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 (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.

【 授权许可】

Unknown