Sclareol modulates free radical production in the retinal rod outer segment by inhibiting the ectopic f1fo-atp synthase

Silvia Ravera, Alfonso Esposito, Paolo Degan, Federico Caicci, Daniela Calzia, Eleonora Perrotta, Lucia Manni, Angela Bisio, Valeria Iobbi, Anna Schito, Carlo Enrico Traverso, Isabella Panfoli

Research output: Contribution to journalArticlepeer-review

Abstract

We have previously shown that the retinal rod outer segments (OS) produce reactive oxygen species in the function of illumination in vitro, establishing a relationship among the extra-mitochondrial oxidative phosphorylation and phototransduction. This source of oxidative stress in the OS can be modulated by polyphenols, acting as inhibitors of F1Fo-ATP synthase. The present study aimed at exploring whether sclareol, a diterpene, interacts with F1Fo-ATP synthase mitigating the light-induced free radical production in the rod OS. Characterization of bovine retinal sections was conducted by immunogold analysis. Reactive oxygen intermediates production, oxygen consumption, the activity of the four respiratory complexes and ATP synthesis were evaluated in purified bovine rod OS. Molecular docking analyses were also conducted. Sclareol reduced free radical production by light-exposed rod OS. Such antioxidant effect was associated with an inhibition of the respiratory complexes and oxygen consumption (OCR), in coupled conditions. Sclareol also inhibited the rod OS ATP synthetic ability. Since the inhibitor effect on respiratory complexes and OCR is not observed in uncoupled conditions, it is supposed that the modulating effect of sclareol on the ectopic oxidative phosphorylation in the rod OS targets specifically the F1Fo-ATP synthase. This hypothesis is confirmed by the in silico molecular docking analyses, which shows that sclareol binds the F1 moiety of ATP synthase with high affinity. In conclusion, a beneficial effect of sclareol can be envisaged as a modulator of oxidative stress in the photoreceptor, a risk factor for the degenerative retinal diseases, suggestive of its potential beneficial action also in vivo.

Original languageEnglish
Pages (from-to)368-375
Number of pages8
JournalFree Radical Biology and Medicine
Volume160
DOIs
Publication statusPublished - Nov 20 2020

Keywords

  • Aerobic metabolism
  • ATP synthase
  • Light
  • Oxidative phosphorylation
  • Respiratory chain complexes
  • Rod outer segment
  • Sclareol
  • Transmission electron microscopy.

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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