The features of activation of free oxidation by α,ω-tetradecanedioic acid in liver mitochondria

Abstract

It was found that α,ω-tetradecanedioic acid (TDA) at the concentration of 0–500 μM doubles the rate of nonphosphorylating respiration (free oxidation) of liver mitochondria in a dose-dependent manner. This effect of TDA is observed in the presence of the excess of EGTA, which eliminates the induction of the Ca2+-dependent nonspecific permeability of the mitochondrial inner membrane (pore opening). An unusually high concentration of cyclosporin A (10 mM) completely eliminates this effect when added to the mitochondria before or after TDA. The stimulatory effect of TDA is not accompanied by inhibition of oxidative ATP synthesis and decrease in the ADP/O ratio, in contrast to the effects of other activators of free oxidation, such as protonophore uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone and palmitic acid. It was shown that neither oligomycin, an inhibitor of H+-ATP synthase, nor ADP, ATP and Pi affected the activity of TDA. This is seen as an evidence that the effect of TDA is not associated with the influence on H+-ATP synthase and it differs from the action of membranotropic uncouplers. In the presence of the lipophilic cation tetraphenylphosphonium (TPP+) cyclosporin A does not affect the TDA-stimulated respiration of mitochondria, but carboxyatractylate and glutamate added after TDA do inhibit the respiration. In addition, under these conditions TDA decreases the rate of oxidative ATP synthesis and reduces the ADP/O ratio. It is assumed that the mechanism of the TDA-induced activation of free oxidation in liver mitochondria in the absence of TPP+ is similar to that of the so-called decouplers and is associated with the switching of the respiratory chain complexes to the idle mode (inner uncoupling).