Malonyl-CoA metabolism in cardiac myocytes

Abstract

(1) Malonyl-CoA is thought to play a signalling role in fuel-selection in cardiac muscle, but the rate at which the concentration of this potential signal can be changed has not previously been investigated. (2) Rapid changes in cellular malonyl-CoA could be observed when rat cardiac myocytes were incubated in glucose-free medium followed by re-addition of 5 mM glucose, or when cells were transferred from a medium containing glucose to a glucose-free medium. On addition of glucose, malonyl-CoA increased by 62% to a new steady-state level, at a rate of at least 0.4 nmol/g dry wt. per min. The half-time of this change was less than 3 min. After removal of glucose the malonyl-CoA content was estimated to decline by 0.43-0.55 nmol/g dry wt. per min. (3) Malonyl-CoA decarboxylase (MDC) is a possible route for disposal of malonyl-CoA. No evidence was obtained for a cytosolic activity of MDC in rat heart where most of the activity was found in the mitochondrial fraction. MDC in the mitochondrial matrix was not accessible to extramitochondrial malonyl-CoA. However, approx. 16% of the MDC activity in mitochondria was overt, in a manner that could not be explained by mitochondrial leakage. It is suggested that this, as yet uncharacterized, overt MDC activity could provide a route for disposal of cytosolic malonyl-CoA in the heart. (4) No activity of the condensing enzyme for the fatty acid elongation system could be detected in any heart subcellular fraction using two assay systems. A previous suggestion [Awan and Saggerson (1993) Biochem. J. 295, 61-66] that this could provide a route for disposal of cytosolic malonyl-CoA in heart should therefore be abandoned.

Malonyl-CoA, a Key Signaling Molecule in Mammalian Cells

“…By contrast, the presence of cytosolic MCD activity in heart was reported (71). Both of these studies (55,71), as well as a third study (30), reported the existence of overt mitochondrial MCD activity, which is between 16% and 23% of the total heart mitochondrial MCD activity and which ought to the accessible to cytosolic malonylCoA. The question of how and where this overt MCD is attached to heart mitochondrial membrane lipids or to membrane proteins remains unresolved.…”

“…In rat heart, MCD activity was observed in a crude mitochondrial fraction but no evidence was found for a cytosolic MCD (55). By contrast, the presence of cytosolic MCD activity in heart was reported (71).…”

Regulation of cardiac malonyl-CoA content and fatty acid oxidation during increased cardiac power

“…It is important to note that the inhibitory site for malonyl-CoA is on the cytosolic side of CPT I (12,15,22,40) and that malonyl-CoA is found in both the cytosol and the mitochondria (12,15,22,40). It is possible that adrenergic stimulation and/or high rates of cardiac energy expenditure cause a selective decrease in cytosolic acetyl-CoA or result in selective alterations in the activity or cellular location of cytosolic ACC or MCD, which lead to reduced production or greater clearance of cytosolic malonyl-CoA.…”

Inactivation of the AMP-activated protein kinase by glucose in cardiac myocytes: a role for the pentose phosphate pathway

“…Conversely, increases in carbohydrate fuels together with an increase in insulin results in decreased fatty acid oxidation and an increase in malonyl-CoA appears to be the key factor in this reverse Randle Cycle effect. The content of malonylCoA in perfused heart or in cardiac myocytes is increased by glucose [11] and it has been suggested that the increase in malonylCoA is due to an increased supply of acetyl-CoA for ACC [34]. We propose that dephosphorylation and activation of ACC in response to glucose (Figure 3) additionally contributes to this reverse Randle Cycle effect.…”