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. 2024 Oct 25;120(16):1996–2016. doi: 10.1093/cvr/cvae231

Figure 3.

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.