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

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 F(1)F(0)-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 F(1)F(0)-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.

Cardiac energy metabolism: models of cellular respiration.

The heart requires a large amount of energy to sustain both ionic homeostasis and contraction. Under normal conditions, adenosine triphosphate (ATP) production meets this demand. Hence, there is a complex regulatory system that adjusts energy production to meet this demand. However, the mechanisms for this control are a topic of active debate. Energy metabolism can be divided into three main stages: substrate delivery to the tricarboxylic acid (TCA) cycle, the TCA cycle, and oxidative phosphorylation. Each of these processes has multiple control points and exerts control over the other stages. This review discusses the basic stages of energy metabolism, mechanisms of control, and the mathematical and computational models that have been used to study these mechanisms.