Alcohol inhibits the activation of NAD-linked dehydrogenases by calcium in brain and heart mitochondria

Abstract

The effect of ethanol on the Ca 2+-dependent activation of mitochondrial 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 free calcium when respiring on non-saturating concentrations of NAD-linked substrates. The stimulation of oxidative phosphorylation by Ca 2+ was correlated with an increase of the mitochondrial matrix free calcium concentration ([Ca 2+] m), as measured by fura-2, and with an increased reduction of the mitochondrial NAD)P) pool, indicating an activation of Ca 2+-dependent dehydrogenases. Sodium inhibited Ca 2+-dependent stimulation of state 3 respiration and NAD(P) reduction as a result of stimulation of Ca 2+ efflux through the Na +/Ca 2+ antiporter which reduced the steady-state value of [Ca 2+] m. Ethanol stimulated the Na +/Ca 2+ antiporter both in brain and heart mitochondria. As a result of this stimulation, ethanol, at pharmacological concentrations (50–300 mM), enhanced the sodium-dependent reduction of [Ca 2+] m, and thus attenuated the activation of NAD-linked dehydrogenases and the stimulation of oxidative phosphorylation, by submicromolar concentrations of Ca 2+, both in brain and heart mitochondria. This pharmacological effect of ethanol, 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.