Effect of Ca2+on cardiac mitochondrial energy production is modulated by Na+and H+dynamics
- 1 June 2007
- journal article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 292 (6), C2004-C2020
- https://doi.org/10.1152/ajpcell.00271.2006
Abstract
The energy production of mitochondria in heart increases during exercise. Several works have suggested that calcium acts at multiple control points to activate net ATP production in what is termed “parallel activation”. To study this, a computational model of mitochondrial energy metabolism in the heart has been developed that integrates the Dudycha-Jafri model for the tricarboxylic acid cycle with the Magnus-Keizer model for mitochondrial energy metabolism and calcium dynamics. The model improves upon the previous formulation by including an updated formulation for calcium dynamics, and new descriptions of sodium, hydrogen, phosphate, and ATP balance. To this end, it incorporates new formulations for the calcium uniporter, sodium-calcium exchange, sodium-hydrogen exchange, the F1F0-ATPase, and potassium-hydrogen exchange. The model simulates a wide range of experimental data, including steady-state and simulated pacing protocols. The model suggests that calcium is a potent activator of net ATP production and that as pacing increases energy production due to calcium goes up almost linearly. Furthermore, it suggests that during an extramitochondrial calcium transient, calcium entry and extrusion cause a transient depolarization that serve to increase NADH production by the tricarboxylic acid cycle and NADH consumption by the respiration driven proton pumps. The model suggests that activation of the F1F0-ATPase by calcium is essential to increase ATP production. In mitochondria very close to the release sites, the depolarization is more severe causing a temporary loss of ATP production. However, due to the short duration of the depolarization the net ATP production is also increased.Keywords
This publication has 68 references indexed in Scilit:
- A Biophysical Model of the Mitochondrial Respiratory System and Oxidative PhosphorylationPLoS Computational Biology, 2005
- Distribution of Mitochondrial NADH Fluorescence Lifetimes: Steady-State Kinetics of Matrix NADH InteractionsBiochemistry, 2005
- Metabolic Network Control of Oxidative PhosphorylationPublished by Elsevier BV ,2003
- Intracellular Na+ regulation in cardiac myocytesCardiovascular Research, 2003
- Capillary endothelial surface layer selectively reduces plasma solute distribution volumeAmerican Journal of Physiology-Heart and Circulatory Physiology, 2000
- Mathematical model of compartmentalized energy transfer: Its use for analysis and interpretation of 31P-NMR studies of isolated heart of creatine kinase deficient miceMolecular and Cellular Biochemistry, 1998
- Compartmentalized energy transfer in cardiomyocytes: use of mathematical modeling for analysis of in vivo regulation of respirationBiophysical Journal, 1997
- Na(+)-dependent Ca2+ efflux mechanism of heart mitochondria is not a passive Ca2+/2Na+ exchangerAmerican Journal of Physiology-Cell Physiology, 1994
- Cellular concentrations of enzymes and their substratesJournal of Theoretical Biology, 1990
- Evidence from Inhibitor Studies for Conformational Changes of Citrate SynthaseEuropean Journal of Biochemistry, 1981