Molecular system bioenergetics: regulation of substrate supply in response to heart energy demands

FFAs are taken up by a family of plasma membrane proteins (fatty acid transporter protein (FATP1), fatty acid translocase (CD36)) and in cytoplasm associated with fatty acid binding protein (FABP). FFAs are esterified to acyl-CoA via fatty acyl-CoA synthetase. The resulting acyl-CoA is then transported through the inner membrane of the mitochondrion, via the exchange of CoA for carnitine by carnitine palmitolyltransferase I (CPT I). Acylcarnitine is then transported by carnitine acylcarnitine translocase into the mitochondrial matrix where a reverse exchange takes place through the action of carnitine palmitoyltransferae II (CPT II). Once inside the mitochondrion acyl-CoA is a substrate for the β-oxidation pathway, resulting in acetyl-CoA production. Each round of β-oxidation produces 1 molecule of NADH, 1 molecule of FADH2 and 1 molecule of acetyl-CoA. Acetyl-CoA enters the TCA cycle, where it is further oxidized to CO2 with the concomitant generation of 3 molecules of NADH, 1 molecule of FADH2 and 1 molecule of ATP. Acetyl-CoA, which is formed in the mitochondrial matrix, can be transferred into the cytoplasm with participation of carnitine, carnitine acetyltransferases and carnitine acetyltranslocase (carnitine acetylcarnitine carrier complex, CAC). Glucose (GLU) is taken up by glucose transporter-4 (GLUT-4) and enters the Embden-Meyerhof pathway, which converts glucose via a series of reactions into 2 molecules of pyruvate (PYR). As a result of these reactions, a small amount of ATP and NADH are produced. G6P – glucose 6-phosphate; HK – hexokinase; PFK – phosphofructokinase; GLY – glycogen; F1,6diP – fructose-1,6-bisphosphate; GAPDH – glyceralhehydephosphate dehydrogenase; 1,3DPG – 1,3 diphosphoglycerate. The redox potential of NADH is transferred into the mitochondrial matrix via the malate–aspartate shuttle. OAA – oxaloacetate; Glut – glutamate; αKG –α-ketoglutarate; ASP – aspartate. Malate generated in the cytosol enters the matrix in exchange for α-ketoglutarate (αKG) and can be used to produce matrix NADH. Matrix oxaloacetate (OAA) is returned to the cytosol by conversion to ASP and exchange with glutamate (Glut). Most of the metabolic energy derived from glucose can come from the entry of pyruvate into the Krebs cycle and oxidative phosphorylation via acetyl-CoA production. NADH and FADH2 are oxidized in the respiratory chain (complexes I, II, III and IV). These pathways occur under aerobic conditions. Under anaerobic conditions, pyruvate can be converted to lactate. Feedback regulation of substrate supply occurs in the following way. A glucose–fatty acid cycle (Randle hypothesis): if glucose and FFAs are both present, FFAs inhibit the transport of glucose across the plasma membrane, acyl-CoA oxidation increases the mitochondrial ratios of acetyl-CoA/CoA and of NADH/NAD+, which inhibit the pyruvate dehydrogenase (PDH) complex, and increased citrate (produced in the Krebs cycle) can inhibit phosphofructokinase (PFK). These changes would slow down oxidation of glucose and pyruvate (PYR) and increase glucose-6-phosphate (G6P), which would inhibit hexokinase (HK), and decrease glucose transport. The mitochondrial creatine kinase (miCK) catalyses the direct transphosphorylation of intramitochondrially produced ATP and cytosolic creatine (Cr) into ADP and phosphocreatine (PCr). ADP enters the matrix space to stimulate oxidative phosphorylation, while PCr is transferred via cytosolic Cr/PCr shuttle to be used by functional coupling of CK with ATPases (acto-myosin ATPase and ion pumps); If the workload increases, ATP production and respiration are increased due to feedback signalling via the creatine kinase (CK) system, leading to decreased mitochondrial content of acetyl-CoA, which is transferred into the cytoplasm with participation of carnitine acetyl carrier (CAC). Acetyl-CoA carboxylase (ACC) is responsible for converting acetyl-CoA to malonyl-CoA, a potent inhibitor of CPT I, with the aim to avoid overloading the mitochondria with fatty acid oxidation intermediates, when the workload is decreased. Inactivation of ACC occurs via phosphorylation catalysed by AMP-activated protein kinase (AMPK). Phosphorylation and inactivation of ACC leads to a decrease in the concentration of malonyl-CoA. A fall in malonyl-CoA levels disinhibits CPT I, resulting in increased fatty acid oxidation. Malonyl-CoA is also converted back into acetyl-CoA in the malonyl-CoA decarboxylase (MCD) reaction. Increase in the workload increases the rate of acetyl-CoA consumption and that automatically decreases the malonyl-CoA content. The ACC and MCD regulation occur under stress conditions when the AMP/ATP ratios are increased, but are unlikely to occour under normal work-load conditions of the heart. Thus, AMPK may be envisaged as a modulator, under situations of cellular stress, rather than as a master on–off switch of fatty acid oxidation.

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Molecular system bioenergetics: regulation of substrate supply in response to heart energy demands. (2006) Valdur Saks, et al. J Physiol. 2006 Dec 15;577(Pt 3):769-777. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

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