Fig. 1. MPC as a metabolic branch point.

a Glucose is converted to pyruvate via glycolysis. Pyruvate can be transported to the mitochondria through the MPC or reduced to lactate in the cytosol by lactate dehydrogenase (LDH). Inside the mitochondria, pyruvate can either be oxidised to acetyl-CoA by the pyruvate dehydrogenase (PDH) or carboxylated to oxaloacetate by pyruvate carboxylase (PC). Acetyl-CoA and oxaloacetate can enter the TCA cycle and generate the reducing equivalents NADH and FADH₂ used by the electron transport chain (ETC) to generate ATP. b Decreased MPC expression alone is sufficient to cause metabolic cardiac remodelling, hypertrophic growth and ultimately heart failure. Mice genetically engineered to have decreased cardiomyocyte MPC1/2 divert glucose into the pentose phosphate pathway that generates five carbon sugars such as ribose 5-phosphate, a precursor for nucleotide synthesis and NADPH, which are necessary for anabolic metabolism and the growth of the myocardium. Shunting of fructose-6P from glycolysis towards the hexosamine biosynthetic pathway generates uridine diphosphate N-acetylglucosamine (UDP-N-GlcNAc) used by glycosyltransferases to transfer N-acetylglucosamine residues to proteins, termed O-GlcNAcylation. Other post-translational modifications are also likely to occur in cells as a result of changes in MPC abundance or activity due to the alterations in the TCA cycle or glycolysis caused by rerouting of pyruvate. ATP levels are maintained in heart with decreased MPC, perhaps because acetyl-CoA derived from ketone bodies is supplied to the TCA cycle, preserving the generation of reducing equivalents necessary for mitochondrial respiration.