Stimulation of myocardial coenzyme A degradation by fatty acids

Abstract

Coenzyme A (CoA) levels were increased in isolated hearts from 537 +/- 14 to 818 +/- 44 nmol/g dry wt by perfusion for 45 min under conditions known to stimulate CoA synthesis (5). Subsequently, perfusion of these hearts with buffer containing glucose (11 mM) and pyruvate (5 mM) for 3 min had no effect on CoA levels (789 +/- 42 nmol/g dry wt). However, perfusion with a buffer containing glucose (11 mM) and palmitate (1.2 mM) decreased CoA levels to 683 +/- 34 nmol/g dry wt within 3 min. This decrease in CoA appeared to occur in the cytosolic compartment with no change in mitochondrial CoA content and was associated with a rise in tissue content of long-chain acyl-CoA. An increased incorporation of fatty acids into triglycerides was associated with the rise in total acyl-CoA suggesting that long-chain acyl-CoA levels were elevated in the cytosolic compartment. Perfusion conditions which maximally increased acyl-CoA levels also maximally stimulated CoA degradation. These observations suggest that the cytosolic degradation of CoA is related to high levels of long-chain acyl-CoA in this compartment. Use of these perfusion conditions in future studies should help define the pathway of CoA degradation and determine the mechanisms which control cellular levels of CoA.

Nudt8 is a novel CoA diphosphohydrolase that resides in the mitochondria

“…In the absence of regulatory mechanisms, the latter subcellular localization would allow Coasy to resynthesize CoA from the phosphopantetheine produced by Nudt8, generating wasteful cycles of CoA synthesis and degradation. Our data indicate that in the kidneys, heart, and liver, organs with high expression of Nudt8 and detectable CoA-degrading activity [13,47,48], Nudt8 levels did not change with the nutritional state. Additional studies will be required to determine whether other potential regulatory mechanisms, including post-translational modifications or regulation by metabolites in the mitochondria, may control the activity of Nudt8 and whether Coasy and Nudt8 actually localize to the same submitochondrial compartment.…”

“…Importantly, the existence of Nudt8 and its CoA-degrading activity may explain how, even in the absence of Nudt19 and any detectable levels of Nudt7, the concentration of CoA could still be significantly decreased in the kidneys of Nudt19 À/À mice during the transition from the fasted to the fed state [13]. Our data indicate that in the kidneys, heart, and liver, organs with high expression of Nudt8 and detectable CoA-degrading activity [13,47,48], Nudt8 levels did not change with the nutritional state. 3A).…”