The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) catalyzes the cataplerotic reaction utilizing mitochondrial GTP (mtGTP) to convert oxaloacetate to phosphoenolpyruvate (PEP), GDP, and CO2 in the mitochondrial matrix. Because of its dependence on mtGTP and since mitochondria lack a GTP transporter, mitochondrial PEP synthesis is enzymatically coupled to the GTP-specific isoform of succinyl-CoA synthetase reaction as a source of GTP. In pancreatic beta-cells, this reaction generates a second messenger coupled to insulin secretion (Stark et al. 2009). In the liver and possibly kidney, the mitochondrial PEP is used for gluconeogenesis and glyceroneogenesis (Stark et al. 2014). This chapter will focus on the mammalian mitochondrial isoform and its relationship to maintaining metabolic homeostasis through the secretion of insulin,...
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