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Special Section On Mitochondrial Modeling and Function

Effect of Ca²⁺ on cardiac mitochondrial energy production is modulated by Na⁺ and H⁺ dynamics

¹Department of Bioinformatics and Computational Biology, George Mason University, Manassas, Virginia; ²Diagnostic Ultrasound, Woodinville, Washington; and ³Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland

Submitted 17 May 2006 ; accepted in final form 1 March 2007

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.

oxidative phosphorylation; tricarboxylic acid cycle; pH; computer model

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