📒 Stark 2014

The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: has it been overlooked1


Phosphoenolpyruvate carboxykinase (PEPCK)

  • Reaction: GTP + oxaloacetate (OAA) → GDP + phosphoenolpyruvate (PEP) + CO₂, requires magnesium (Mg) and manganese (Mn)
  • Cytosolic PEPCK (PEPCK-C): regulated by hormones (stimulated by glucagon and suppressed by insulin), for gluconeogenesis
  • Mitochondrial PEPCK (PEPCK-M): regulated by citric acid cycle (CAC) flux

More about PEPCK-M

  • Limited by mitochondrial GTP from citric acid cycle (CAC) flux of GTP-forming succinyl-CoA synthetase (SCS-GTP)
    • mitochondrial GTP has no way out, unlike mitochondrial ATP
    • PEPCK-M: Sensor of CAC flux as well as the amount of intermediates from mtGTP
    • SCS-GTP/SCS-ATP performing nucleotide diphosphokinase (NDPK) reaction in the mitochodnrial matrix
    • The real NDPK lies in the intermembrane space, feeding mitochondrial GTPases for fission/fusion (Drp1, OPA1)
  • Removal of CAC intermediates (cataplerosis) to balance replenishment of CAC intermediates (anaplerosis)
  • Glucose stimulated insulin secretion (GSIS) in islet beta cells2
  • Provider of a relatively constant supply of PEP
  • PEP regulates both mitochondrial calcium transport and ATP/ADP exchange

Generation of PEP

PEPCK-M is a more direct and more energy-efficient way to generate PEP from OAA.
PEPCK-M pathway (conversion to PEP via PEPCK-M and SCS-GTP)
PEPCK-C/aspartate pathway (transamination to aspartate by AAT)
PEPCK-C/malate pathway (reduction to malate via MDH)
PEPCK-C/citrate pathway (conversion to citrate by citrate synthase)

Gluconeogenic pathways

From lactate, specifically:

Roles of mitochondrial GTP in islet beta cells

Jesinkey et. al 2

  • Triggers and amplifies normal GSIS
  • Cell proliferation
  • Augmented mitochondrial mass
  • Increased insulin granule number, and membrane proximity
  • PEPCK-M biochemically transduces the mtGTP signal out to the cytosol by synthesizing PEP

  1. Stark, R., & Kibbey, R. G. (2014). The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: has it been overlooked?. Biochimica et biophysica acta, 1840(4), 1313–1330. doi:10.1016/j.bbagen.2013.10.033 ↩︎

  2. Jesinkey, S. R., Madiraju, A. K., Alves, T. C., Yarborough, O. H., Cardone, R. L., Zhao, X., Parsaei, Y., et al. (2019). Mitochondrial GTP links nutrient sensing to β cell health, mitochondrial morphology, and insulin secretion independent of oxphos. Cell reports, 28(3), 759-772.e10. ↩︎