An Integrated Model of Pancreatic Beta-Cell Mitochondrial Energy Metabolism and Calcium Dynamics
Abstract Number: 1690-P
Authors: LEONID E. FRIDLYAND, LOUIS H. PHILIPSON
Institutions: Chicago, IL
Results: Mathematical analysis of complex cellular systems provides a quantitative framework within which the control mechanisms of processes can be discussed. However, the proposed models of pancreatic beta-cell metabolic and calcium regulation fall short of a comprehensive explanation of existing data. We have continue our development of an integrated kinetic model of Ca2+ dynamics in the pancreatic beta-cell by including the control of beta-cell mitochondrial bioenergetics and Ca2+ handling by the mitochondria. We have updated a previous model of the regulation of ionic currents in the plasma membrane by employing an experimental characterization of the glucokinase reaction, the conductance of Na+/K+-adenosinetriphosphatase current and other data. The mitochondrial model interrelates the simplified tricarboxylic acid (TCA) cycle model with oxidative phosphorylation, electrical gradient, proton gradient and Ca2+ handling. The kinetic components of the model include the TCA cycle regulating production of NADH and FADH2, which in turn are used by the electron transport chain to establish a proton motive force, driving the F1F0-ATPase. In addition, mitochondrial matrix Ca2+, determined by Ca2+ uniporter and Na+/Ca2+ exchanger activities, regulates activity of the TCA cycle enzymes. The model is described by ordinary differential equations for the time rate of change of cytoplasmic and mitochondrial parameters, including mitochondrial membrane potential, NADH and matrix concentrations of Ca2+. The model can predict the response of Ca2+ oscillations in cytoplasm, respiration, mitochondrial NADH and mitochondrial membrane potential to changes in glucose delivery and several channel inhibitors. The results of modeling reproduce qualitatively and semiquantitatively the steady-state and time-dependent experimental data concerning mitochondrial bioenergetics, Ca2+ dynamics in mitochondria and cytoplasm, respiratory control. The model allows in silico testing of the effects of alterations in mitoxondrial calcium dynamics on beta-cell glucose-stimulating coupling.