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 β-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 O2consumption, adenine nucleotide transport, oxidative phosphorylation, and ATP production by the tricarboxylic acid cycle asd-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 thed-glucose threshold for bursting and continuous spiking. According to our simulations, relatively small changes in mitochondrial membrane potential (∼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 μM at low glucose concentrations that become oscillatory with an amplitude on the order of 0.5 μM during bursting. Abrupt increases in mitochondrial Ca2+concentration >5 μM may occur during continuous electrical activity.