MKT-077 Suppresses the Functional Activity of Isolated Mouse Skeletal Muscle Mitochondria

Abstract

This study demonstrates the effect of the rhodocyanine derivative MKT-077 on the function of isolated mitochondria from mouse skeletal muscle. MKT-077 was shown to dose-dependently inhibit mitochondrial respiration fueled by glutamate/malate (complex I substrates) or succinate (complex II substrate). This effect of MKT-077 was accompanied by a decrease in the membrane potential of organelles and was associated with both inhibition of the activity of complexes I and II of the mitochondrial respiratory chain and an increase in the proton permeability of the inner mitochondrial membrane. Molecular docking revealed sites in mitochondrial respiratory chain complex I that have an affinity for MKT-077 comparable to that of the specific inhibitor rotenone. At a concentration of 5 μM, MKT-077 caused a significant increase in hydrogen peroxide production by skeletal muscle mitochondria. However, 1 μM MKT-077 reduced the pro-oxidant effect of antimycin A. In addition, MKT-077 dose-dependently reduced the ability of mitochondria to uptake and retain calcium ions in the matrix. The article discusses the mechanisms of possible action of MKT-077 on the functioning of skeletal muscle mitochondria and their contribution to the side effects observed during the therapy of pathological conditions in vivo using this rhodocyanine derivative.