Effect of VBIT-4 on the functional activity of isolated mitochondria and cell viability

• Published in: Biochimica et biophysica acta. Biomembranes 2024-06, Vol.1866 (5), p.184329, Article 184329
• Main Authors: Belosludtsev, Konstantin N., Ilzorkina, Anna I., Matveeva, Lyudmila A., Chulkov, Alexander V., Semenova, Alena A., Dubinin, Mikhail V., Belosludtseva, Natalia V.
• Format: Article
• Language: English
• Subjects: electron transport chain; Mitochondria; Mitochondrial membrane potential; Oxidative stress; VBIT-4; VDAC
• ISSN: 0005-2736; 1879-2642; 1879-2642
• DOI: 10.1016/j.bbamem.2024.184329

VBIT-4 is a new inhibitor of the oligomerization of VDAC proteins of the outer mitochondrial membrane preventing the development of oxidative stress, mitochondrial dysfunction, and cell death in various pathologies. However, as a VDAC inhibitor, VBIT-4 may itself cause mitochondrial dysfunction in healthy cells. The article examines the effect of VBIT-4 on the functional activity of rat liver mitochondria and cell cultures. We have demonstrated that high concentrations of VBIT-4 (15–30 μM) suppressed mitochondrial respiration in state 3 and 3UDNP driven by substrates of complex I and II. VBIT-4 induced depolarization of organelles fueled by substrates of complex I but not complex II of the respiratory chain. VBIT-4 has been found to inhibit the activity of complexes I, III, and IV of the respiratory chain. Molecular docking demonstrated that VBIT-4 interacts with the rotenone-binding site in complex I with similar affinity. 15–30 μM VBIT-4 caused an increase in H2O2 production in mitochondria, decreased the Ca2+ retention capacity, but increased the time of Ca2+-dependent mitochondrial swelling. We have found that the incubation of breast adenocarcinoma (MCF-7) with 30 μM VBIT-4 for 48 h led to the decrease of the mitochondrial membrane potential, an increase in ROS production and death of MCF-7 cells. The mechanism of action of VBIT-4 on mitochondria and cells is discussed. [Display omitted] •15–30 μM VBIT-4 suppressed mitochondrial respiration in states 3 and 3UDNP.•15–30 μM VBIT-4 induced a drop in membrane potential upon oxidation of complex I substrates.•15–30 μM VBIT-4 caused overproduction of H2O2 by mitochondria.•30 μM VBIT-4 induced mitochondrial depolarization and ROS production in MCF-7 cells.