Minimal model of beta-cell mitochondrial Ca2+ handling.

Abstract

We develop a simplified, but useful, mathematical model to describe Ca2+ handling by mitochondria in the pancreatic beta-cell. The model includes the following six transport mechanisms in the inner mitochondrial membrane: proton pumping via respiration and proton uptake by way of the F1Fzero-ATPase (adapted from D. Pietrobon and S. Caplan. Biochemistry 24: 5764-5778, 1985), a proton leak, adenine nucleotide exchange, the Ca2+ uniporter, and Na+/Ca2+ exchange. Each mechanism is developed separately into a kinetic model for the rate of transport, with parameters taken from experiments on isolated mitochondrial preparations. These mechanisms are combined in a modular fashion first to describe state 4 (nonphosphorylating) and state 3 (phosphorylating) mitochondria with mitochondrial NADH and Ca2+ concentrations as fixed parameters and then to describe Ca2+ handling with variable mitochondrial Ca2+ concentration. Simulations are compared to experimental measurements and agree well with the threshold for Ca2+ uptake, measured mitochondrial Ca2+ levels, and the influence of Ca2+ on oxygen uptake. In the absence of Ca2+ activation of mitochondrial dehydrogenases, the simulations predict a significant reduction in the rate of production of ATP that involves a "short circuit" via Ca2+ uptake through the uniporter. This effect suggests a potential role for mitochondrial Ca2+ handling in determining the ATP-ADP ratio in the pancreatic beta-cell.