Benzimidazole Derivative NS1619 Inhibits Functioning of Mitochondria Isolated from Mouse Skeletal Muscle

M. V. Dubinin; Дубинин М. В.; A. D. Igoshkina; Игошкина А. Д.; A. A. Semenova; Семенова А. А.; N. V. Mikina; Микина Н. В.; E. I. Khoroshavina; Хорошавина Е. И.; K. N. Belosludtsev; Белослудцев К. Н.

doi:10.31857/S0233475523030064

Benzimidazole Derivative NS1619 Inhibits Functioning of Mitochondria Isolated from Mouse Skeletal Muscle

Authors: Dubinin M.V.¹, Igoshkina A.D.¹, Semenova A.A.¹, Mikina N.V.¹, Khoroshavina E.I.¹, Belosludtsev K.N.¹^,2
Affiliations:
1. Mari State University
2. Institute of Theoretical and Experimental Biophysics, RAS
Issue: Vol 40, No 4 (2023)
Pages: 279-288
Section: Articles
URL: https://journals.rcsi.science/0233-4755/article/view/135014
DOI: https://doi.org/10.31857/S0233475523030064
EDN: https://elibrary.ru/FBJKVF
ID: 135014

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Abstract

The activator of the large-conductance Ca²⁺-activated K⁺ channel (BK_Ca) NS1619 is known to have a pleiotropic action and is able to affect the functioning of other transport systems of the cell and its organelles. In this work, we have studied the effect of this benzimidazole derivative on the functioning of isolated mouse skeletal muscle mitochondria. NS1619 has been shown to dose-dependently inhibit respiration and oxidative phosphorylation of mouse skeletal muscle mitochondria fueled by glutamate/malate (complex I substrates) or succinate (complex II substrate). This action of NS1619 is based on the inhibition of the activity of complexes I, III, and IV of the respiratory chain of organelles, as well as ATP synthase and is accompanied by a dose-dependent decrease in the membrane potential of organelles fueled by the above substrates or ATP. In addition, NS1619 significantly reduces the ability of mitochondria to uptake and retain calcium ions in the matrix. At the same time, we noted the antioxidant effect of NS1619 expressed in a decrease in the production of hydrogen peroxide by skeletal muscle mitochondria fueled by glutamate and malate. The mechanisms of the possible toxic effects of NS1619 on skeletal muscle mitochondrial function and its contribution to the side effects observed in the treatment of muscle pathologies in vivo are discussed.

Keywords

skeletal muscle mitochondria, NS1619, oxidative phosphorylation, respiratory chain, calcium, reactive oxygen species

References

González-Sanabria N., Echeverría F., Segura I., Alvarado-Sánchez R., Latorre R. 2021. BK in double-membrane organelles: A biophysical, pharmacological, and functional survey. Front. Physiol. 12, 761474.
Singh H., Rong L., Bopassa J., Meredith A., Stefani E., Toro L. 2013. MitoBK-Ca is encoded by the KCNMA1 gene, and a splicing sequence defines its mitochondrial location. Proc. Natl. Acad. Sci. 110, 10836–10841.
Wrzosek A., Augustynek B., Żochowska M., Szewczyk A. 2021. mitochondrial potassium channels as druggable targets. Biomolecules. 10 (8), 1200.
Checchetto V., Leanza L., De Stefani D., Rizzuto R., Gulbins E., Szabo I. 2021. Mitochondrial K+ channels and their implications for disease mechanisms. Pharmacol. Ther. 227, 107874.
Xu W., Liu Y., Wang S., McDonald T., Van Eyk J.E., Sidor A., O’Rourke B. 2002. Cytoprotective role of Ca2+- activated K+ channels in the cardiac inner mitochondrial membrane. Science. 298, 1029–1033.
Kulawiak B., Kudin A.P., Szewczyk A., Kunz W.S. 2008. BK channel openers inhibit ROS production of isolated rat brain mitochondria. Exp. Neurol. 212, 543–547.
Heinen A., Aldakkak M., Stowe D.F., Rhodes S.S., Riess M.L., Varadarajan S.G., Camara A.K. 2007. Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2+-sensitive K+ channels. Am. J. Physiol. Heart Circ. Physiol. 293, H1400–H1407.
Wang X., Yin C., Xi L., Kukreja R.C. 2004. Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice. Am. J. Physiol. Heart Circ. Physiol. 287, H2070–H2077.
Du X., Carvalho-De-Souza J.L., Wei C., Carrasquel-Ursulaez W., Lorenzo Y., Gonzalez N., Kubota T., Staisch J., Hain T., Petrossian N., Xu M., Latorre R., Bezanilla F., Gomez C.M. 2020. Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia. Proc. Natl. Acad. Sci. USA. 117, 6023–6034.
Debska G., Kicinska A., Dobrucki J., Dworakowska B., Nurowska E., Skalska J., Dolowy K., Szewczyk A. 2003. Large-conductance K+ channel openers NS1619 and NS004 as inhibitors of mitochondrial function in glioma cells. Biochem. Pharmacol. 65 (11), 1827–1834.
Kicinska A., Szewczyk A. 2004. Large-conductance potassium cation channel opener NS1619 inhibits cardiac mitochondria respiratory chain. Toxicol. Mech. Methods, 14 (1–2), 59–61.
Łukasiak A., Skup A., Chlopicki S., Łomnicka M., Kaczara P., Proniewski B., Szewczyk A., Wrzosek A. 2016. SERCA, complex I of the respiratory chain and ATP-synthase inhibition are involved in pleiotropic effects of NS1619 on endothelial cells. Eur. J. Pharmacol. 786, 137–147.
Park W.S., Kang S.H., Son Y.K., Kim N., Ko J.H., Kim H.K., Ko E.A., Kim C.D., Han J. 2007. The mitochondrial Ca2+-activated K+ channel activator, NS 1619 inhibits L-type Ca2+ channels in rat ventricular myocytes. Biochem. Biophys. Res. Commun. 362 (1), 31–36.
Dubinin M.V., Starinets V.S., Belosludtseva N.V., Mikheeva I.B., Chelyadnikova Y.A., Igoshkina A.D., Vafina A.B., Vedernikov A.A., Belosludtsev K.N. 2022. BKCa activator ns1619 improves the structure and function of skeletal muscle mitochondria in duchenne dystrophy. Pharmaceutics. 14, 2336.
Dubinin M.V., Talanov E.Y., Tenkov K.S., Starinets V.S., Mikheeva I.B., Sharapov M.G., Belosludtsev K.N. 2020. Duchenne muscular dystrophy is associated with the inhibition of calcium uniport in mitochondria and an increased sensitivity of the organelles to the calcium-induced permeability transition. Biochim. Biophys. Act-a. Mol. Basis Dis. 1866 (5), 165674.
Dubinin M.V., Svinin A.O., Vedernikov A.A., Starinets V.S., Tenkov K.S., Belosludtsev K.N., Samartsev V.N. 2019. Effect of hypothermia on the functional activity of liver mitochondria of grass snake (Natrixnatrix): Inhibition of succinate-fueled respiration and K+ transport, ROS-induced activation of mitochondrial permeability transition. J. Bioenerg. Biomembr. 51 (3), 219–229.
Chance B., Williams G.R. 1955. Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. J. Biol. Chem. 217 (1), 383–393.
Pollard A.K., Craig E.L., Chakrabarti L. 2016. Mitochondrial complex I activity measured by spectrophotometry is reduced across all brain regions in ageing and more specifically in neurodegeneration. PLoS One. 11(6), e0157405.
Spinazzi M., Casarin A., Pertegato V., Salviati L., Angelini C. 2012. Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nat. Protoc. 7 (6), 1235–1246.
Venediktova N., Solomadin I., Nikiforova A., Starinets V., Mironova G. 2021. functional state of rat heart mitochondria in experimental hyperthyroidism. Int. J. Mol. Sci. 22, 11744.
Dubinin M.V., Sharapov V.A., Ilzorkina A.I., Efimov S.V., Klochkov V.V., Gudkov S.V., Belosludtsev K.N. 2022. Comparison of structural properties of cyclosporin A and its analogue alisporivir and their effects on mitochondrial bioenergetics and membrane behavior. Biochim. Biophys. Acta Biomembr. 1864 (9), 183972.
Dubinin M.V., Starinets V.S., Talanov E.Y., Mikheeva I.B., Belosludtseva N.V., Belosludtsev K.N. 2021. Alisporivir improves mitochondrial function in skeletal muscle of mdx mice but suppresses mitochondrial dynamics and biogenesis. Int. J. Mol. Sci. 22, 9780.
Heinen A., Camara A.K., Aldakkak M., Rhodes S.S., Riess M.L., Stowe D.F. 2007. Mitochondrial Ca2+-induced K+ influx increases respiration and enhances ROS production while maintaining membrane potential. Am. J. Physiol. Cell Physiol. 292 (1), C148–C156.
Bosetti F., Baracca A., Lenaz G., Solaini, G. 2004. Increased state 4 mitochondrial respiration and swelling in early post-ischemic reperfusion of rat heart. FEBS Lett. 563 (1–3), 161–164.
Zorov D.B., Juhaszova M., Sollott S. J. 2014. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 94 (3), 909–950.
Андреев А.Ю., Кушнарева Ю.Е., Мерфи Э.Н., Старков А.А. 2015 Митохондриальный метаболизм активных форм кислорода: десять лет спустя. Биохимия. 5 (80), 612–630.
Rasola A., Bernardi P. 2011. Mitochondrial permeability transition in Ca2+-dependent apoptosis and necrosis. Cell Calcium. 50, 222–233.
Дубинин М.В., Белослудцев К.Н. 2019. Таксономические особенности механизмов специфического транспорта Cа2+ в митохондриях. Биол. мембраны. 36 (4), 231–241.
Белослудцев К.Н., Дубинин М.В., Белослудцева Н.В., Миронова Г.Д. 2019. Транспорт ионов Ca2+ митохондриями: механизмы, молекулярные структуры и значение для клетки. Биохимия. 6 (84), 759–775.
Olesen S. P., Munch E., Moldt P., Drejer J. 1994. Selective activation of Ca2+-dependent K+ channels by novel benzimidazolone. Eur. J. Pharmacol. 251 (1), 53–59.