Effect of bedaquiline on the functions of rat liver mitochondria

The paper considers the effects of bedaquiline (BDQ), an antituberculous preparation of the new generation, on rat liver mitochondria. It was shown that 50 mu M BDQ inhibited mitochondrial respiration measured with substrates of complexes I and II (glutamate/malate and succinate/rotenone systems respectively) in the states V-3 and V-DNP. At the same time, at concentrations below 50 mu M, BDQ slightly stimulated respiration with substrates of complex I in the state V-2. BDQ was also found to suppress, in a dose-dependent manner, the activity of complex II and the total activity of complexes II + III of the mitochondrial transport chain. It was discovered that at concentrations up to 10 mu M, BDQ inhibited H2O2 production in mitochondria. BDQ (10-50 mu M) suppressed the opening of Ca-2+ -dependent CsA-sensitive mitochondrial permeability transition pore. The latter was revealed experimentally as the inhibition of Ca2+ /P-i-dependent swelling of mitochondria, suppression of cytochrome c release, and an increase in the Ca2+ capacity of the organelles. BDQ also decreased the rate of mitochondrial energy-dependent K+ transport, which was evaluated by the energy-dependent swelling of mitochondria in a K+ buffer and DNP-induced K+ efflux from the organelles. The possible mechanisms of BDQ effect of rat liver mitochondria are discussed.