Malonyl-CoA Accumulation as a Compensatory Cytoprotective Mechanism in Cardiac Cells in Response to 7-Ketocholesterol-Induced Growth Retardation

Abstract

The major oxidized product of cholesterol, 7-Ketocholesterol (7KCh), causes cellular oxidative damage. In the present study, we investigated the physiological responses of cardiomyocytes to 7KCh. A 7KCh treatment inhibited the growth of cardiac cells and their mitochondrial oxygen consumption. It was accompanied by a compensatory increase in mitochondrial mass and adaptive metabolic remodeling. The application of [U-13C] glucose labeling revealed an increased production of malonyl-CoA but a decreased formation of hydroxymethylglutaryl-coenzyme A (HMG-CoA) in the 7KCh-treated cells. The flux of the tricarboxylic acid (TCA) cycle decreased, while that of anaplerotic reaction increased, suggesting a net conversion of pyruvate to malonyl-CoA. The accumulation of malonyl-CoA inhibited the carnitine palmitoyltransferase-1 (CPT-1) activity, probably accounting for the 7-KCh-induced suppression of β-oxidation. We further examined the physiological roles of malonyl-CoA accumulation. Treatment with the inhibitor of malonyl-CoA decarboxylase, which increased the intracellular malonyl-CoA level, mitigated the growth inhibitory effect of 7KCh, whereas the treatment with the inhibitor of acetyl-CoA carboxylase, which reduced malonyl-CoA content, aggravated such a growth inhibitory effect. Knockout of malonyl-CoA decarboxylase gene (Mlycd−/−) alleviated the growth inhibitory effect of 7KCh. It was accompanied by improvement of the mitochondrial functions. These findings suggest that the formation of malonyl-CoA may represent a compensatory cytoprotective mechanism to sustain the growth of 7KCh-treated cells.

Case report: A novel 5'-UTR-exon1-intron1 deletion in MLYCD in an IVF child with malonyl coenzyme A decarboxylase deficiency and literature review

“…Malonyl-CoA decarboxylase (MCD, E.C.4.1.1.9) activity deficiency caused by MLYCD gene mutation contributes to Malonic aciduria (OMIM 248360) ( 1 ). When MCD activity is affected, malonyl coenzyme A accumulates in the cytoplasm and strongly and effectively inhibits carnitine palmitoyltransferase (CPT1) in the outer mitochondrial membrane, resulting in the inability of long-chain fatty acids to enter the mitochondrial matrix for further β-oxidation and energy supply ( 2 ). Elevation of plasma malonylcarnitine (C3DC) level and urinary malonate is unique to this autosomal recessive disorder.…”

Molecular Mechanisms of Cardiac Development and Disease

“…Malonyl-CoA inhibits CPT-1, which is involved in the fatty acid uptake into the mitochondria and β-oxidation. The accumulation of malonyl-CoA might therefore represent a cardiac cell protective mechanism upon 7KCh treatment to reduce the use of fatty acids as fuel molecules for β-oxidation [10]. The group around Josep Julve deciphers in part the molecular mechanism by which FTY720, an FDA-approved sphingosine derivative, improves mitochondrial function in cardiomyocytes.…”