Functional activity and morphology of isolated rat cardiac mitochondria under calcium overload. Effect of naringin

Abstract

The role of calcium-dependent processes in cardiac physiology and pathophysiology as well as the function of mitochondria as a regulator of myocyte calcium homeostasis have been extensively discussed. The aim of the present work was to evaluate the mechanism(s) of modulation of respiratory activity, morphology, permeability transition, and membrane potential of rat cardiac mitochondria by exogenous Ca2+ ions in the absence or in the presence of the plant flavonoid glucoside naringin. Low free Ca2+ concentrations (40–250 nM) effectively inhibited the respiratory activity of rat heart mitochondria: decreased the rates of succinate-dependent V2 and ADP-stimulated V3 respiration, remaining unaffected the efficacy of oxygen consumption. In the presence of high exogenous Ca2+ ion concentrations (the free Ca2+ concentration was 550 µM), we observed a dramatic increase in mitochondrial heterogeneity in size and electron density that was connected with calcium-induced opening of the mitochondrial permeability transition pores (MPTP) and membrane depolarization, observed at free Ca2+ concentrations of 150 to 750 µM. As compared to rat liver mitochondria, the sensitivity to Ca2+ of rat heart mitochondria was much lower in the case of MPTP opening and much higher in the case of respiration inhibition. Naringin, occurring naturally in citrus fruits, partially prevented Ca2+-induced rat cardiac mitochondrial morphological transformations (200 µM), dose-dependently inhibited the respiratory activity of mitochondria (10–75 µM) in the absence or in the presence of calcium ions and promoted membrane potential dissipation and mitochondria swelling in the absence of calcium ions but inhibited calcium-induced MPTP formation at higher concentrations (75 µM).