MINIMAL MODEL OF BETA-CELL MITOCHONDRIAL CA2+ HANDLING

We develop a simplified, but useful, mathematical model to describe Ca 2+ handling by mitochondria in the pancreatic beta-cell. The model inc ludes the following six transport mechanisms in the inner mitochondria l membrane: proton pumping via respiration and proton uptake by way of the F1F0-ATPase (adapted from D. Pietrobon and S. Caplan. Biochemistr y 24: 5764-5778, 1985), a proton leak, adenine nucleotide exchange, th e Ca2+ uniporter, and Na+/Ca2+ exchange. Each mechanism is developed s eparately into a kinetic model for the rate of transport, with paramet ers taken from experiments on isolated mitochondrial preparations. The se mechanisms are combined in a modular fashion first to describe stat e 4 (nonphosphorylating) and state 3 (phosphorylating) mitochondria wi th mitochondrial NADH and Ca2+ concentrations as fixed parameters and then to describe Ca2+ handling with variable mitochondrial Ca2+ concen tration. Simulations are compared to experimental measurements and agr ee well with the threshold for Ca2+ uptake, measured mitochondrial Ca2 + levels, and the influence of Ca2+ on oxygen uptake. In the absence o f Ca2+ activation of mitochondrial dehydrogenases, the simulations pre dict a significant reduction in the rate of production of ATP that inv olves a ''short circuit'' via Ca2+ uptake through the uniporter. This effect suggests a potential role for mitochondrial Ca2+ handling in de termining the ATP:ADP ratio in the pancreatic beta-cell.