A Thermodynamically-Consistent Model for ATP Production in Mitochondria

Abstract

AbstractLife is based on energy conversion. In the nervous system, in particular, significant amounts of energy are needed to maintain synaptic transmission and homeostasis. To a large extent, neurons depend on oxidative phosphorylation in mitochondria to meet their high energy demand. To develop a comprehensive understanding of the metabolic demands in neuronal signaling, accurate models of ATP production in mitochondria are required. Here, we present a thermodynamically-consistent model of ATP production in mitochondria based on previous work [1, 2, 3, 4]. The significant improvement of the model is that the reaction rate constants are set, so detailed balance is satisfied. Moreover, using thermodynamic considerations, the dependence of the reaction rate constants on membrane potential, pH, and substrate concentrations are explicitly provided. These constraints assure us the model is physically-plausible. We provide a complete and detailed derivation of ATP production in mitochondria. Furthermore, we explore different parameter regimes to understand in which conditions ATP production or its export are the limiting step in making ATP available in the cytosol. The outcomes reveal that, under physiological conditions, ATP production is the limiting step and not its export. Finally, we analyze the portion of the total volume taken up by the membranes and study the functional effect this compression can have on the availability of ATP in the cytosol. A compression of approximately 50% of the intermembrane space or the matrix can increase the amount of ATP in the cytosol by 2-6%. This model lays the foundation for future studies of the internal mitochondrial physiology and metabolism in neurons using Monte-Carlo techniques to simulate the biochemical interactions that take place in the mitochondrial compartments.