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Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore

The permeability transition pore in mitochondria (MPTP) and the ATP-binding cassette transporters (АВС transporters) in cell membranes provide the efflux of low-molecular compounds across mitochondrial and cell membranes, respectively. The inhibition of ABC transporters, especially of those related...

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Autores principales: Fedotcheva, Tatiana, Shimanovsky, Nikolai, Fedotcheva, Nadezhda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502193/
https://www.ncbi.nlm.nih.gov/pubmed/36135908
http://dx.doi.org/10.3390/membranes12090890
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author Fedotcheva, Tatiana
Shimanovsky, Nikolai
Fedotcheva, Nadezhda
author_facet Fedotcheva, Tatiana
Shimanovsky, Nikolai
Fedotcheva, Nadezhda
author_sort Fedotcheva, Tatiana
collection PubMed
description The permeability transition pore in mitochondria (MPTP) and the ATP-binding cassette transporters (АВС transporters) in cell membranes provide the efflux of low-molecular compounds across mitochondrial and cell membranes, respectively. The inhibition of ABC transporters, especially of those related to multi drug resistance (MDR) proteins, is an actively explored approach to enhance intracellular drug accumulation and increase thereby the efficiency of anticancer therapy. Although there is evidence showing the simultaneous effect of some inhibitors on both MDR-related proteins and mitochondrial functions, their influence on MPTP has not been previously studied. We examined the participation of verapamil and quinidine, classified now as the first generation of MDR modulators, and avermectin, which has recently been actively studied as an MDR inhibitor, in the regulation of the MPTP opening. In experiments on rat liver mitochondria, we found that quinidine lowered and verapamil increased the threshold concentrations of calcium ions required for MPTP opening, and that they both decreased the rate of calcium-induced swelling of mitochondria. These effects may be associated with the positive charge of the drugs and their aliphatic properties. Avermectin not only decreased the threshold concentration of calcium ions, but also by itself induced the opening of MPTP and the mitochondrial swelling inhibited by ADP and activated by carboxyatractyloside, the substrate and inhibitor of adenine nucleotide translocase (ANT), which suggests the involvement of ANT in the process. Thus, these data indicate an additional opportunity to evaluate the effectiveness of MDR modulators in the context of their influence on the mitochondrial-dependent apoptosis.
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spelling pubmed-95021932022-09-24 Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore Fedotcheva, Tatiana Shimanovsky, Nikolai Fedotcheva, Nadezhda Membranes (Basel) Article The permeability transition pore in mitochondria (MPTP) and the ATP-binding cassette transporters (АВС transporters) in cell membranes provide the efflux of low-molecular compounds across mitochondrial and cell membranes, respectively. The inhibition of ABC transporters, especially of those related to multi drug resistance (MDR) proteins, is an actively explored approach to enhance intracellular drug accumulation and increase thereby the efficiency of anticancer therapy. Although there is evidence showing the simultaneous effect of some inhibitors on both MDR-related proteins and mitochondrial functions, their influence on MPTP has not been previously studied. We examined the participation of verapamil and quinidine, classified now as the first generation of MDR modulators, and avermectin, which has recently been actively studied as an MDR inhibitor, in the regulation of the MPTP opening. In experiments on rat liver mitochondria, we found that quinidine lowered and verapamil increased the threshold concentrations of calcium ions required for MPTP opening, and that they both decreased the rate of calcium-induced swelling of mitochondria. These effects may be associated with the positive charge of the drugs and their aliphatic properties. Avermectin not only decreased the threshold concentration of calcium ions, but also by itself induced the opening of MPTP and the mitochondrial swelling inhibited by ADP and activated by carboxyatractyloside, the substrate and inhibitor of adenine nucleotide translocase (ANT), which suggests the involvement of ANT in the process. Thus, these data indicate an additional opportunity to evaluate the effectiveness of MDR modulators in the context of their influence on the mitochondrial-dependent apoptosis. MDPI 2022-09-16 /pmc/articles/PMC9502193/ /pubmed/36135908 http://dx.doi.org/10.3390/membranes12090890 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fedotcheva, Tatiana
Shimanovsky, Nikolai
Fedotcheva, Nadezhda
Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore
title Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore
title_full Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore
title_fullStr Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore
title_full_unstemmed Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore
title_short Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore
title_sort involvement of multidrug resistance modulators in the regulation of the mitochondrial permeability transition pore
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502193/
https://www.ncbi.nlm.nih.gov/pubmed/36135908
http://dx.doi.org/10.3390/membranes12090890
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