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

doi:10.1016/j.ejcb.2024.151398

Molecular mechanisms of naringenin modulation of mitochondrial permeability transition acting on F₁F_O-ATPase and counteracting saline load-induced injury in SHRSP cerebral endothelial cells

Eur J Cell Biol. 2024 Feb 15;103(2):151398. doi: 10.1016/j.ejcb.2024.151398. Online ahead of print.

Authors

Salvatore Nesci¹, Cristina Algieri², Matteo Antonio Tallarida³, Rosita Stanzione⁴, Saverio Marchi⁵, Donatella Pietrangelo⁶, Fabiana Trombetti², Luca D'Ambrosio⁷, Maurizio Forte⁴, Maria Cotugno⁴, Ilaria Nunzi⁵, Rachele Bigi⁸, Loredana Maiuolo⁹, Antonio De Nino⁹, Paolo Pinton¹⁰, Giovanni Romeo¹¹, Speranza Rubattu¹²

Affiliations

¹ Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia 40064, Italy. Electronic address: salvatore.nesci@unibo.it.
² Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia 40064, Italy.
³ RINA Consulting - Centro Sviluppo Materiali SpA, Via di Castel Romano 100, Rome, 00128, Italy.
⁴ IRCCS Neuromed, Pozzilli 86077, Italy.
⁵ Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona 60126, Italy.
⁶ Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome 00189, Italy.
⁷ Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina 04100, Italy.
⁸ Department of Neuroscience, Mental Health, and Sensory Organs, Sapienza University, Rome 00189, Italy.
⁹ Department of Chemistry and Chemical Technologies, University of Calabria, Cosenza 87036, Italy.
¹⁰ Translational Research Center, Maria Cecilia Hospital GVM Care & Research, Cotignola 48033, Italy; Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy.
¹¹ Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Bologna 40126, Italy.
¹² IRCCS Neuromed, Pozzilli 86077, Italy; Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome 00189, Italy.

PMID: 38368729
DOI: 10.1016/j.ejcb.2024.151398

Abstract

Naringenin (NRG) was characterized for its ability to counteract mitochondrial dysfunction which is linked to cardiovascular diseases. The F₁F_O-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 F₁F_O-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 F₁F_O-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.

Keywords: F(1)F(O)-ATPase; ROS; SHRSP; mitochondria; naringenin; permeability transition pore.