Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Tr-57 Treatment of SUM159 Cells Induces Mitochondrial Dysfunction without Affecting Membrane Potential

Artem Mishukov
ORCID logo ,
Ekaterina Mndlyan
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Alexey V. Berezhnov
ORCID logo ,
Margarita Kobyakova
ORCID logo ,
Yana Lomovskaya
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Ekhson Holmuhamedov
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Irina Odinokova
* ORCID logo
Version 1 : Received: 4 December 2023 / Approved: 6 December 2023 / Online: 6 December 2023 (08:55:20 CET)

A peer-reviewed article of this Preprint also exists.

Mishukov, A.; Mndlyan, E.; Berezhnov, A.V.; Kobyakova, M.; Lomovskaya, Y.; Holmuhamedov, E.; Odinokova, I. TR-57 Treatment of SUM159 Cells Induces Mitochondrial Dysfunction without Affecting Membrane Potential. Int. J. Mol. Sci. 2024, 25, 1193. Mishukov, A.; Mndlyan, E.; Berezhnov, A.V.; Kobyakova, M.; Lomovskaya, Y.; Holmuhamedov, E.; Odinokova, I. TR-57 Treatment of SUM159 Cells Induces Mitochondrial Dysfunction without Affecting Membrane Potential. Int. J. Mol. Sci. 2024, 25, 1193.

Abstract

Recent works identified ClpXP, mitochondrial caseinolytic protease, as the only target of imipridones - new class of antitumor agents. Our study of the mechanism of imipridone derivative TR-57 action in SUM159 human breast cancer cells demonstrated mitochondrial fragmentation, degradation of mitochondrial mtDNA and mitochondrial dysfunction, due to inhibition of Complex I and Complex II activity. Complete inhibition of oxidative phosphorylation accom-panied with 90, 94, 88 and 87% decrease in the content of Complex I, II, III and IV proteins, respectively. The content of the FOF1-ATPase subunits decreased sharply by approximately 35% after 24 hours and remained unchanged up to 72 hours of incubation with TR-57. At the same time, a disappearance of the ATPIF1, natural inhibitor of mitochondrial FOF1-ATPase observed after 24 h exposure to TR-57. ATPase inhibitor oligomycin had no effect on the mitochondrial membrane potential in intact SUM159, whereas it caused a 65% decrease in TR-57-treated cells. SUM159 cells incubated with TR57 up to 72 hours retained the level of proteins facilitating the ATP transfer across the mitochondrial membranes: VDAC1 expression was not affected, while expression of ANT-1/2 and APC2 increased by 20% and 40%, respectively. Thus, our results suggest that alt-hough TR-57 treatment lead to complete inhibition of respiratory chain activity of SUM159 cells, hydrolysis of cytoplasmic ATP by reversal activity of FOF1-ATPase supports mitochondrial polarization.

Keywords

TR-57; SUM159 TNBC cells; respiratory complexes: mitochondrial membrane potential; FoF1-ATPase; IF1; calcium-regulated mitochondrial ATP-Mg/Pi carrier

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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