Model of β-cell mitochondrial calcium handling and electrical activity.: II.: Mitochondrial variables

In the preceding article [Am. J. Physiol. 274 (Cell Physiol. 43): C1158-C1173, 1998], we describe the development of a kinetic model for the interaction of mitochondrial Ca2+ handling and electrical activity in the pancreatic beta-cell. Here we describe further results of those simulations, focusing on mitochondrial variables, the rate of respiration, and fluxes of metabolic intermediates as a function of D-glucose concentration. Our simulations predict relatively smooth increases of O-2 consumption, adenine nucleotide transport, oxidative phosphorylation, and ATP production by the tricarboxylic acid cycle as D-glucose concentrations are increased from basal to 20 mM. On the other hand, we find that the active fraction of pyruvate dehydrogenase saturates, due to increases in matrix Ca2+, near the onset of bursting electrical activity and that the NADH/NAD(+) ratio in the mitochondria increases by roughly an order of magnitude as glucose concentrations are increased. The mitochondrial ATP/ADP ratio increases by factor of <2 between the D-glucose threshold for bursting and continuous spiking. According to our simulations, relatively small changes in mitochondrial membrane potential (similar to 1 mV) caused by uptake of Ca2+ are sufficient to alter the cytoplasmic ATP/ADP ratio and influence ATP-sensitive K+ channels in the plasma membrane. In the simulations, these cyclic changes in the mitochondrial membrane potential are due to synchronization of futile cycle of Ca2+ from the cytoplasm through mitochondria via Ca2+ uniporters and Na+/Ca2+ exchange. Our simulations predict steady mitochondrial Ca2+ concentrations on the order of 0.1 mu M at low glucose concentrations that become oscillatory with an amplitude on the order of 0.5 mu M during bursting. Abrupt increases in mitochondrial Ca2+ concentration >5 mu M may occur during continuous electrical activity.