Activation of mitochondrial fatty acid oxidation by calcium. Conversion to the energized state.

Abstract

The oxidation of [l-Wlpalmitate by isolated rat liver mitochondria was increased by calcium chloride, and was quantitatively accounted for by an increased production of ketone bodies facetoacetate plus /3-hydroxybutyrate).'%02 production was depressed by Ca2+.These changes were associated with an elevated /3-hydroxybutyrate:acetoacetate ratio, reflecting an increased mitochondrial NADH:NAD+ ratio.Calculations reveal that the additional NADH produced via the increase in fatty acid oxidation was more than required for Ca 2+ transport and for the increased reduction of acetoacetate.The results indicate that the effect of Ca2+ on fatty acid oxidation was responsible for the elevation of the mitochondrial NADH:NAD+ ratio.The effects of Ca'+ on palmitate oxidation and the pyridine nucleotide oxidation-reduction state showed an absolute requirement for carnitine, CoA, ATP, and Mg2+.These effects exhibited half-maximal response under the standard incubation conditions, at approximately 80 nmol of Ca2+/ mg of protein, a value which proved to be a function of the pH of the system.These Ca*+-dependent changes were accompanied by an elevated steady state rate of oxygen consumption, measured after the completion of Ca2+ accumulation, and increased ATP production.Ca*+ uptake studies in the presence of palmitate, CoA, carnitine, phosphate, Mg2+, and ATP showed that the initial rapid transport of Ca2+ was completed in 2 min.The fihydroxybutyrate:acetoacetate ratio decreased during this initial period of Ca*+ transport and subsequently increased.The Ca2+-dependent decline and subsequent elevation of the ATP concentration paralleled the temporal changes in the P-hydroxybutyrate to acetoacetate ratio.However, an elevation in the rate of ketone body production was observed at the onset of Ca2+ addition.This rate decreased slightly after 2 min, but remained greater than the control.The Ca*+ transport inhibitor ruthenium red, added at the time of Ca2+ addition, completely blocked the Ca*+-dependent elevations of ketone body production and the P-hydroxybu-