Post-translational Acetylation Control of Cardiac Energy Metabolism

Abstract

Perturbations in myocardial energy substrate metabolism are key contributors to the pathogenesis of heart diseases. However, the underlying causes of these metabolic alterations remain poorly understood. Recently, post-translational acetylation-mediated modification of metabolic enzymes has emerged as one of the important regulatory mechanisms for these metabolic changes. Nevertheless, despite the growing reports of a large number of acetylated cardiac mitochondrial proteins involved in energy metabolism, the functional consequences of these acetylation changes and how they correlate to metabolic alterations and myocardial dysfunction are not clearly defined. This review summarizes the evidence for a role of cardiac mitochondrial protein acetylation in altering the function of major metabolic enzymes and myocardial energy metabolism in various cardiovascular disease conditions.

Keywords: fatty acid oxidation; glucose oxidation; lysine acetylation; mitochondria; sirtuins; succinylation.

Figure 1

The process of protein lysine acetylation/acylation and deacetylation/deacylation. KAT1, lysine acetyltransferase; NAA60, N-α-acetyltransferase 60; CBP, CREB-binding protein; SIRT, sirtuin, GNAT, GCN5-related N-acetyltransferases; MYST, MYST family acetyltransferase; GCN5L1, General control of amino acid synthesis 5 (GCN5) like-1; ACAT1, acetyl-CoA acetyltransferase; AC, lysine Acetylation; SU, succinylation; MU, malonylation.

Figure 2

Metabolic proteins subjected to acetylation control in the heart. AC, lysine acetylation; GLUT4, glucose transporter isoform 4; SLC7A5/8, solute carrier family-7; SLC25A44, solute carrier family-25; SLC16, solute carrier family-16; MCT, monocarboxylate transporter 1; CD36, cluster of differentiation 36; FABPpm, plasma membrane fatty acid-binding protein; MCD, malonyl CoA decarboxylase; ACC, acetyl CoA carboxylase; PDH, pyruvate dehydrogenase; LCAD, long-chain acyl CoA dehydrogenase; β-HAD, β-hydroxyacyl CoA dehydrogenase; KAT, 3-ketoacyl-coa thiolase; ECH, enoyl-CoA hydratase; FAS, fatty acyl CoA synthase; CPT-1, carnitine palmitoyltransferase 1; CPT-2, carnitine palmitoyltransferase-2; CT, carnitine acyl translocase; BCAA, branched-chain amino acids; BCATm, mitochondrial branched-chain aminotransferase; BCADH, branched-chain amino acid dehydrogenase; β-OHB, β-hydroxybutyrate; BDH-1, 3-hydroxybutyrate dehydrogenase 1; SCOT, 3-ketoacid CoA transferase; CS, citrate synthase; ISDH, iso-citrate dehydrogenase; α-KGDH, alpha-ketoglutarate dehydrogenase; SCS, succinate CoA synthetase; MDH, malate dehydrogenase; SDH, succinate dehydrogenase; FH, fumarate hydratase; OAA, oxaloacetate; MCD, malonyl CoA decarboxylase; ACON, aconitase; HK, hexose kinase; GA3P, glyceraldehyde 3-phosphate; 3PG: 3-phosphoglycerate; PGM, Phosphoglycerate mutase; PK, pyruvate kinase; CoQ, coenzyme Q; Cytc: cytochrome C; FAD/FADH₂, flavin adenine dinucleotide; NAD/NADH2, nicotinamide adenine dinucleotide.

Figure 3

Contributing factors to mitochondrial protein hyperacetylation.