Advances in myocardial energy metabolism: metabolic remodelling in heart failure and beyond

Abstract

The very high energy demand of the heart is primarily met by adenosine triphosphate (ATP) production from mitochondrial oxidative phosphorylation, with glycolysis providing a smaller amount of ATP production. This ATP production is markedly altered in heart failure, primarily due to a decrease in mitochondrial oxidative metabolism. Although an increase in glycolytic ATP production partly compensates for the decrease in mitochondrial ATP production, the failing heart faces an energy deficit that contributes to the severity of contractile dysfunction. The relative contribution of the different fuels for mitochondrial ATP production dramatically changes in the failing heart, which depends to a large extent on the type of heart failure. A common metabolic defect in all forms of heart failure [including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved EF (HFpEF), and diabetic cardiomyopathies] is a decrease in mitochondrial oxidation of pyruvate originating from glucose (i.e. glucose oxidation). This decrease in glucose oxidation occurs regardless of whether glycolysis is increased, resulting in an uncoupling of glycolysis from glucose oxidation that can decrease cardiac efficiency. The mitochondrial oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in HFpEF and diabetic cardiomyopathies myocardial fatty acid oxidation increases, while in HFrEF myocardial fatty acid oxidation either decreases or remains unchanged. The oxidation of ketones (which provides the failing heart with an important energy source) also differs depending on the type of heart failure, being increased in HFrEF, and decreased in HFpEF and diabetic cardiomyopathies. The alterations in mitochondrial oxidative metabolism and glycolysis in the failing heart are due to transcriptional changes in key enzymes involved in the metabolic pathways, as well as alterations in redox state, metabolic signalling and post-translational epigenetic changes in energy metabolic enzymes. Of importance, targeting the mitochondrial energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac function and cardiac efficiency in the failing heart.

Keywords: Fatty acid oxidation; Glucose oxidation; HFpEF; HFrEF; Ketone oxidation.

Figure 1

Depiction of major metabolic pathways and its associated key enzymes involved in metabolism of glucose, fatty acids, ketones, and BCAA in the heart. Glucose metabolism can be divided as glycolysis and downstream pyruvate metabolism/glucose oxidation. Fatty acid oxidation can be regulated by the endogenous inhibitor malonyl-CoA. Ketone oxidation is depicted using the major form of ketone bodies, βOHB. BCAA oxidation includes oxidation of leucine, isoleucine, and valine. All four metabolic substrates are converted to acetyl-CoA for entering the TCA cycle to generate reduced equivalent NADH and FADH2, which will enter the ETC and generate a proton gradient across the mitochondrial membrane to drive the action of ATP synthase for ATP genesis. GLUT1/4, glucose transporter 1/4; MCT4, monocarboxylate transporter 4; PFK, phosphofructokinase; MPC, mitochondrial pyruvate carrier; PDH, pyruvate dehydrogenase; PDK, PDH kinase; ACC, acetyl-CoA carboxylase; MCD, malonyl-CoA decarboxylase; CD36/FAT, fatty acid transporter; CPT1, carnitine palmitoyltransferase 1; LCAD, long-chain acyl-CoA dehydrogenase; ECH, enoyl CoA hydratase; βHAD, 3-OH-acyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase; BCAA, branched-chain amino acids; BCATm, mitochondrial BCAA amimotransferase; BCKDH, branched-chain α-ketoacid dehydrogenase; LAT, L-type amino acid transporters; βOHB, β-hydroxybutyrate; BDH1, βOHB dehydrogenase 1; SCOT, succinyl-CoA:3-ketoacid CoA transferase; TCA, tricarboxylic acid; NADH, nicotinamide adenine dinucleotide; FADH2, flavin adenine dinucleotide; ETC, electron transport chain; ADP, adenosine diphosphate; ATP, adenosine triphosphate.

Figure 2

Alterations of myocardial energy metabolism in heart failure. Summary chart showing the alterations of five major energy metabolic pathways, including glycolysis, glucose oxidation, fatty acid oxidation, ketone oxidation, branched-chain amino acid (BCAA) oxidation in three different types of HFrEF, HFpEF, heart failure associated with obesity, and T2D. Arrow pointing upward indicates the corresponding pathway is stimulated, and arrow pointing downward indicates the corresponding pathway is suppressed.

Figure 3

Molecular mechanisms contributing to altered energy metabolism in heart failure. Changes and disruptions in energy metabolism in heart failure are governed by four distinct molecular mechanisms: mitochondrial function, substrate control, transcriptional control, and post-translational modifications. (i) Mitochondrial dysfunction in heart failure encompasses reduced transcriptional regulation of mitochondrial biogenesis, increased ROS production, impaired mitofission, sustained mitophagy, and enhanced autophagic cell death of cardiomyocytes. (ii) Regulation of carbon flux through metabolic pathways in the heart relies on tight control of CoA and its derivatives. In heart failure, the acetyl-CoA pool resulting from fatty acid oxidation can allosterically inhibit metabolic pathways through enzymes like PDH, thiolase, and ACAT. (iii) Transcriptional regulation in cardiac metabolism involves PPARs, ERRs, PGC-1α, and HIF-1α. (iv) PTMs play a crucial role in modulating the activities of mitochondrial enzymes and are implicated in heart failure progression. The small bubbles attached to specific proteins with letters P, A, S, M are representing PTMs. The representation of each letter are phosphorylation, P; acetylation, A; succinylation, S; malonylation, M. GLUT1/4, glucose transporter 1/4; PFK, phosphofructokinase; MPC, mitochondrial pyruvate carrier; PDH, pyruvate dehydrogenase; PDK, PDH kinase; CD36/FAT, fatty acid transporter; CPT1, carnitine palmitoyltransferase 1; LCAD, long-chain acyl-CoA dehydrogenase; βHAD, 3-OH-acyl-CoA dehydrogenase; MCAD, medium chain acyl-CoA dehydrogenase; βOHB, β-hydroxybutyrate; BDH1, βOHB dehydrogenase 1; SCOT, succinyl-CoA:3-ketoacid CoA transferase; MCT1, monocarboxylate transporter 1; ROS, reactive oxygen species; TCA, tricarboxylic acid; NADH, nicotinamide adenine dinucleotide; FADH2, flavin adenine dinucleotide; ETC, electron transport chain; ADP, adenosine diphosphate; ATP, adenosine triphosphate; SDR, short chain dehydrogenase; IDH2, isocitrate dehydrogenase; NAMPT, nicotinamide phosphoribosyltransferase; NAM, nicotinamide; TFAM, transcription factor A, mitochondrial; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α; MAPK, mitogen-activated protein kinase; PPAR, peroxisome proliferator-activated receptors; RXR, the retinoid X receptor; ERR, oestrogen-related receptor; HIF1, hypoxia-induced factor-1; HRE, hypoxia-response element.

Figure 4

Current available pharmacological therapies that target cardiac energy metabolism. Collection of drugs that target different metabolic pathways through modifying the action of key enzymes involved. PDK inhibitor alleviates the inhibitory action of PDK on PDH, thus can stimulate glucose oxidation. MCT4 inhibition decreases lactate efflux, which can redirect glycolytic carbon flux into mitochondrial pyruvate oxidation/glucose oxidation. CD36 inhibition decrease fatty acid uptake into myocardium. Both CPT1 inhibitors and MCD inhibitors decrease the action of CPT1 for uptake of fatty acids into mitochondria. β-oxidation inhibitors interferes with the action of KAT, one of the major β-oxidation enzymes. Ketone therapy includes, ketone ester, βOHB infusion, SGLT2 inhibitor all which increases circulating βOHB levels, thus elevated accessibility of βOHB for further uptake and oxidation by the heart. BCKDK inhibitors alleviate the inhibitory action of BCKDK, thus stimulating the action of BCKDH and inducing the flux of BCAA oxidation. GLUT1/4, glucose transporter 1/4; MCT4, monocarboxylate transporter 4; PFK, phosphofructokinase; MPC, mitochondrial pyruvate carrier; PDH, pyruvate dehydrogenase; PDK, PDH kinase; ACC, acetyl-CoA carboxylase; MCD, malonyl-CoA decarboxylase; CD36/FAT, fatty acid transporter; CPT1, carnitine palmitoyltransferase 1; LCAD, long-chain acyl-CoA dehydrogenase; ECH, enoyl CoA hydratase; βHAD, 3-OH-acyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase; BCAA, branched-chain amino acids; BCATm, mitochondrial BCAA amimotransferase; BCKDH, branched-chain α-ketoacid dehydrogenase; BCKDK, BCKDH kinase; LAT, L-type amino acid transporters; βOHB, β-hydroxybutyrate; BDH1, βOHB dehydrogenase 1; SCOT, succinyl-CoA:3-ketoacid CoA transferase; SGLT2, sodium-glucose co-transporter 2; TCA, tricarboxylic acid; NADH; nicotinamide adenine dinucleotide; FADH2, flavin adenine dinucleotide; ETC, electron transport chain; ADP, adenosine diphosphate; ATP, adenosine triphosphate.