ALCOHOL INHIBITS THE ACTIVATION OF NAD-LINKED DEHYDROGENASES BY CALCIUM IN BRAIN AND HEART-MITOCHONDRIA

The effect of ethanol on the Ca2+-dependent activation of mitochondria l dehydrogenases in rat brain and heart mitochondria was investigated. ADP-stimulated respiration of isolated brain and heart mitochondria ( state 3) was stimulated further by submicromolar concentrations of fre e calcium when respiring on non-saturating concentrations of NAD-linke d substrates. The stimulation of oxidative phosphorylation by Ca2+ was correlated with an increase of the mitochondrial matrix free calcium concentration ([Ca2+](m)), as measured by fura-2, and with an increase d reduction of the mitochondrial NAD(P) pool, indicating an activation of Ca2+-dependent dehydrogenases. Sodium inhibited Ca2+-dependent sti mulation of state 3 respiration and NAD(P) reduction as a result of st imulation of Ca2+ efflux through the Na+/Ca2+ antiporter which reduced the steady-state value of [Ca2+](m). Ethanol stimulated the Na+/Ca2antiporter both in brain and heart mitochondria. As a result of this s timulation, ethanol, at pharmacological concentrations (50-300 mM), en hanced the sodium-dependent reduction of [Ca2+](m), and thus attenuate d the activation of NAD-linked dehydrogenases and the stimulation of o xidative phosphorylation, by submicromolar concentrations of Ca2+, bot h in brain and heart mitochondria. This pharmacological effect of etha nol, on brain and heart mitochondria, may be responsible, in part, for the acute and chronic effects of ethanol on brain and heart function and metabolism.