PALMITATE OXIDATION BY THE MITOCHONDRIA FROM VOLUME-OVERLOADED RAT HEARTS

In this work, an attempt was made to identify the reasons of impaired long-chain fatty acid utilization that was previously described in vol ume-overloaded rat hearts. The most significant data are the following : (1) The slowing down of long-chain fatty acid oxidation in severely hypertrophied hearts cannot be related to a feedback inhibition of car nitine palmitoyltransferase I from an excessive stimulation of glucose oxidation since, because of decreased tissue levels of L-carnitine, g lucose oxidation also declines in volume-overloaded hearts. (2) While, in control hearts, the estimated intracellular concentrations of free carnitine an in the range of the respective K-m of mitochondrial CPT I, a kinetic limitation of this enzyme could occur in hypertrophied he arts due to a 40% decrease in free carnitine. (3) The impaired palmita te oxidation persists upon the isolation of the mitochondria from thes e hearts even in presence of saturating concentrations of L-carnitine. In contrast, the rates of the conversion of both palmitoyl-CoA and pa lmitoylcarnitine into acetyl-CoA are unchanged. (4) The kinetic analys es of palmitoyl-CoA synthase and carnitine palmitoyltransferase I reac tions do not reveal any differences between the two mitochondrial popu lations studied. On the other hand, the conversion of palmitate into p almitoylcarnitine proves to be substrate inhibited already at physiolo gical concentrations of exogenous palmitate. The data presented in thi s work demonstrate that, during the development of severe cardiac hype rtrophy, a fragilization of the mitochondrial outer membrane may occur . The functional integrity of this membrane seems to be further deteri orated by increasing concentrations of free fatty acids which gives ri se to an impaired cooperation between palmitoyl-CoA synthase and carni tine palmitoyltransferase I. In intact myocardium, the utilization of the in situ generated palmitoyl-Coa can be further slowed down by decr eased intracellular concentrations of free carnitine.