A thermodynamically-consistent model for ATP production in mitochondria

AO_SCPLOWBSTRACTC_SCPLOWLife is based on energy conversion. In particular, in the nervous system 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 (Pekkurnaz and Wang, 2022). For 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 (Pietrobon and Caplan, 1985; Magnus and Keizer, 1997; Metelkin et al., 2006; Garcia et al., 2019). The significant improvement of the model is that the reaction rate constants are set such that 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 the model is physically plausible. Furthermore, we explore different parameter regimes to understand in which conditions ATP production or its export are the limiting steps in making ATP available in the cytosol. The outcomes reveal that, under the conditions used in our simulations, ATP production is the limiting step and not its export. Finally, we performed spatial simulations with nine 3D realistic mitochondrial reconstructions and linked the ATP production rate in the cytosol with morphological features of the organelles. 1. SO_SCPLOWUMMARYC_SCPLOWIn this work, Garcia et al present a thermodynamically consistent model for ATP production in mitochondria, in which reaction rate constants are set such that detailed balance is satisfied. Simulations revealed that ATP production, but not its export, is the limiting step, and simulations with 3D mitochondrial reconstructions linked the ATP production rate in the cytosol with the morphological features of the organelles.