Wu, Yang, Vinnakota, Beard, 2007

Model Status

This CellML version of the model runs in OpenCell and COR to replicate the results of the original MATLAB code. The units are consistent. Note, to run the model the step size must be small in the order of 1e-6 and the tolerances are in the order of 1e-12.

Model Structure

ABSTRACT: A computational model of mitochondrial metabolism and electrophysiology is introduced and applied to analysis of data from isolated cardiac mitochondria and data on phosphate metabolites in striated muscle in vivo. This model is constructed based on detailed kinetics and thermodynamically balanced reaction mechanisms and a strict accounting of rapidly equilibrating biochemical species. Since building such a model requires introducing a large number of adjustable kinetic parameters, a correspondingly large amount of independent data from isolated mitochondria respiring on different substrates and subject to a variety of protocols is used to parameterize the model and ensure that it is challenged by a wide range of data corresponding to diverse conditions. The developed model is further validated by both in vitro data on isolated cardiac mitochondria and in vivo experimental measurements on human skeletal muscle. The validated model is used to predict the roles of NAD and ADP in regulating the tricarboxylic acid cycle dehydrogenase fluxes, demonstrating that NAD is the more important regulator. Further model predictions reveal that a decrease of cytosolic pH value results in decreases in mitochondrial membrane potential and a corresponding drop in the ability of the mitochondria to synthesize ATP at the hydrolysis potential required for cellular function.

The original paper reference is cited below:

Computer Modeling of Mitochondrial Tricarboxylic Acid Cycle, Oxidative Phosphorylation, Metabolite Transport, and Electrophysiology, Fan Wu, Feng Yang, Kalyan C. Vinnakota, Daniel A. Beard, 2007, Journal of Biological Chemistry, volume 282, no. 34. PubMed ID: 17591785

Schematic diagram of the model components. The illustrated components include tricarboxylic acid cycle reactions, oxidative phosphorylation reactions, substrate and cation transport reactions, and passive permeation fluxes. External reactions are not illustrated here. The tricarboxylic acid reactions are numbered 1-11. 1, pyruvate dehydrogenase; 2, citrate synthase; 3, aconitase; 4, isocitrate dehydrogenase; 5, alpha-ketoglutarate dehydrogenase; 6, succinyl-CoA synthetase; 7, succinate dehydrogenase; 8, fumarase; 9, malate dehydrogenase; 10, nucleoside diphosphokinase; 11, glutamate oxaloacetate transaminase.