Myocardial Metabolism in Heart Failure

Figures

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  Fig. 1. Overview of energy metabolism pathways in a normal heart. Fatty acids are transported into the cardiomyocyte via CD36 and fatty acid transporter protein (FAT) and undergo esterification to form fatty acyl-CoA. The acyl group is transferred to carnitine by carnitine palmitoyltransferase 1 (CPT-1) to form long-chain acylcarnitine and is transported into the mitochondria where it is converted back to fatty acyl-CoA by CPT-2. The fatty acyl-CoA then undergoes beta-oxidation to form acetyl-CoA. The activity of CPT1 is regulated by malonyl-CoA which is formed through carboxylation of acetyl-CoA by acetyl-CoA carboxylase (ACC) and reverted to acetyl-CoA by malonyl-CoA decarboxylase (MCD). The activity of ACC is regulated by phosphorylation via energy sensors such as AMP-activated protein kinase (AMPK). Glucose enters the cardiomyocyte through glucose-transporters-1 or 4 (GLUT-1, GLUT-4). Free glucose is phosphorylated into glucose-6-phosphate (glucose-6P), which can enter different pathways such as glycolysis, pentose phosphate pathway, or the hexosamine biosynthesis pathway. Glycolysis remains the main pathway, producing pyruvate, reduced nicotinamide adenine dinucleotide (NADH), and a…

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  Fig. 2. Overview of AMP-kinase, sirtuin-1 (SIRT1), peroxisome proliferator-activated receptors (PPARs), and PPAR-gamma coactivator (PGC-1α) pathways. The mTOR signalling pathway regulates multiple anabolic cellular processes, including protein synthesis, cellular proliferation, cell metabolism, and autophagy. CAMKK, calcium/calmodulin-dependent protein kinase 2; LKB1, liver kinase B1; NF-kB, nuclear factor kappa B; MnSOD, manganese superoxide dismutase; eNOS, endothelial nitric oxide synthase; ERR, oestrogen-related receptors; NRF, nuclear-related factor; ULK1, Unc-51-like autophagy activating kinase; mTOR, mechanistic target of rapamycin, PFK, phosphofructokinase

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  Fig. 3. Overview of mitochondrial function including ATP generation, redox signalling, and calcium handling. In a healthy cardiomyocyte, the ryanodine receptor (RyR2) of the sarcoplasmic reticulum (SR) is in close proximity with the mitochondria, where the mitochondrial calcium uniporter (MCU) is located. This facilitates a specific concentration of free Ca2+ in the SR-mitochondria interface to enable mitochondrial uptake of cytosolic Ca2+, a process that sustains mitochondrial metabolism for cardiomyocyte contraction. Mitochondrial Ca2+ efflux is mediated by the mitochondrial Na+/Ca2+ exchanger (NCLX) located near the sarcoplasmic reticulum Ca2+ ATPases (SERCA). Cytosolic Ca2+ levels are also regulated by other transporters in the plasma membrane such as the sodium-calcium exchanger (NCX), Ca2+ ATPases, and sodium-hydrogen exchanger (NHE). The mitochondrial permeability transition pore (mPTP) located in the inner mitochondrial membrane is normally closed and opens when stimulated by mitochondrial Ca2+ overload—this results in mitochondrial osmotic swelling and dissipation of the mitochondrial inner membrane potential, ultimately resulting in cell death. Reactive oxygen species such as…