The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: Has it been overlooked?

The mitochondrial isoform of phosphoenolpyruvate carboxylase (PEPCK-M) plays an important role in glucose homeostasis. As PEPCK-M is constitutively expressed and dependent upon mitochondrial GTP (mtGTP), it is well disposed to link the mitochondrial energy sensing signal “mtGTP” with insulin secretion in the pancreas (left) or glucose production (right) in the liver. Glucose that enters the β-cells of the pancreas (left) is degraded to phosphoenolpyruvate (PEP) during glycolysis and metabolized to pyruvate. Pyruvate that enters the TCA cycle by pyruvate dehydrogenase (PDH) will generate GTP via direct synthesis by SCS-GTP. Anaplerotic pyruvate entry by pyruvate carboxylase (PC) will generate oxaloacetate. PEPCK-M will then consume oxaloacetate and GTP to produce PEP. In contrast to the pancreas, the liver has two PEPCK isoforms: cytosolic (PEPCK-C) and mitochondrial (PEPCK-M) and both produce PEP when there is adequate TCA flux (right). PEP can then be used for gluconeogenesis. The mtGTP/PEPCK-M pathway is a hormone-independent gluconeogenic pathway. GDH glutamate dehydrogenase.182