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

Giuseppe Maulucci, Giuseppe Tringali, Maria Elisabetta Clementi, Michela Pizzoferrato, Giada Bianchetti, Anna Brancato

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

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 H2 O2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H2 O2-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 (∆Ψm ) at physio-logical 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.
Lingua originaleEnglish
pagine (da-a)503-517
Numero di pagine15
RivistaBiomedicines
Volume10
DOI
Stato di pubblicazionePubblicato - 2022

Keywords

  • ARPE-19 (human-RPE cell line)
  • Apoptosis
  • Idebenone
  • Mitochondria
  • Nuclear factor erythroid 2-related factor (Nrf2)
  • Oxidative stress

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