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

Abstract

The activator of the large-conductance Ca2+-activated K+ channel (BKCa) 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.