1. Effect of VBIT-4 on the functional activity of isolated mitochondria and cell viability.
- Author
-
Belosludtsev KN, Ilzorkina AI, Matveeva LA, Chulkov AV, Semenova AA, Dubinin MV, and Belosludtseva NV
- Subjects
- Animals, Humans, Rats, Membrane Potential, Mitochondrial drug effects, MCF-7 Cells, Molecular Docking Simulation, Hydrogen Peroxide pharmacology, Hydrogen Peroxide metabolism, Calcium metabolism, Voltage-Dependent Anion Channels metabolism, Oxidative Stress drug effects, Rats, Wistar, Male, Cell Survival drug effects, Mitochondria, Liver metabolism, Mitochondria, Liver drug effects
- Abstract
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 3U
DNP 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 H2 O2 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF