The Synergistic Impact of Glycolysis, Mitochondrial OxPhos, and PEP Cycling on ATP Production in Beta Cells

We present a model of ATP production in pancreatic beta cells, focusing on ATP dynamics within the bulk cytosol, submembrane region, and microdomains near KATP channels. ATP is generated through glycolysis, the mitochondrial oxidative phosphorylation (OxPhos) and glycolytic pyruvate kinase-mediated phosphoenolpyruvate (PEP) production, supported by PEP cycling between mitochondria and the cytosol. The model examines ATP production in relation to Ca2+ oscillations, elucidating their interdependent dynamics. Our findings demonstrate that both mitochondrial OxPhos and PEP-mediated ATP production contribute substantially to cellular ATP levels. Specifically, glycolysis and mitochondrial OxPhos are crucial for the initial (first-phase) increase in bulk and subplasmalemmal ATP, effectively “filling up” the ATP pool in beta cells. In the second phase, coordinated cycling between OxPhos and PEP pathways enables cost-effective fine-tuning of ATP levels, with localized effects in the KATP channel microdomains. This model addresses and clarifies the recent debate regarding the mechanisms by which sufficient ATP concentrations are achieved to close KATP channels in glucose-stimulated beta cells, offering novel insights into the regulation of energy production and KATP channel activity.