European Journal of Cell Biology (Jun 2024)

Molecular mechanisms of naringenin modulation of mitochondrial permeability transition acting on F1FO-ATPase and counteracting saline load-induced injury in SHRSP cerebral endothelial cells

  • Salvatore Nesci,
  • Cristina Algieri,
  • Matteo Antonio Tallarida,
  • Rosita Stanzione,
  • Saverio Marchi,
  • Donatella Pietrangelo,
  • Fabiana Trombetti,
  • Luca D’Ambrosio,
  • Maurizio Forte,
  • Maria Cotugno,
  • Ilaria Nunzi,
  • Rachele Bigi,
  • Loredana Maiuolo,
  • Antonio De Nino,
  • Paolo Pinton,
  • Giovanni Romeo,
  • Speranza Rubattu

Journal volume & issue
Vol. 103, no. 2
p. 151398

Abstract

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Naringenin (NRG) was characterized for its ability to counteract mitochondrial dysfunction which is linked to cardiovascular diseases. The F1FO-ATPase can act as a molecular target of NRG. The interaction of NRG with this enzyme can avoid the energy transmission mechanism of ATP hydrolysis, especially in the presence of Ca2+ cation used as cofactor. Indeed, NRG was a selective inhibitor of the hydrophilic F1 domain displaying a binding site overlapped with quercetin in the inside surface of an annulus made by the three α and the three β subunits arranged alternatively in a hexamer. The kinetic constant of inhibition suggested that NRG preferred the enzyme activated by Ca2+ rather than the F1FO-ATPase activated by the natural cofactor Mg2+. From the inhibition type mechanism of NRG stemmed the possibility to speculate that NRG can prevent the activation of F1FO-ATPase by Ca2+. The event correlated to the protective role in the mitochondrial permeability transition pore opening by NRG as well as to the reduction of ROS production probably linked to the NRG chemical structure with antioxidant action. Moreover, in primary cerebral endothelial cells (ECs) obtained from stroke prone spontaneously hypertensive rats NRG had a protective effect on salt-induced injury by restoring cell viability and endothelial cell tube formation while also rescuing complex I activity.

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