A Biophysically Based Mathematical Model for the Kinetics of Mitochondrial Calcium Uniporter

Ca²⁺ transport through mitochondrial Ca²⁺ uniporter is the primary Ca²⁺ uptake mechanism in respiring mitochondria. Thus, the uniporter plays a key role in regulating mitochondrial Ca²⁺. Despite the importance of mitochondrial Ca²⁺ to metabolic regulation and mitochondrial function, and to cell physiology and pathophysiology, the structure and composition of the uniporter functional unit and kinetic mechanisms associated with Ca²⁺ transport into mitochondria are still not well understood. In this study, based on available experimental data on the kinetics of Ca²⁺ transport via the uniporter, a mechanistic kinetic model of the uniporter is introduced. The model is thermodynamically balanced and satisfactorily describes a large number of independent data sets in the literature on initial or pseudo-steady-state influx rates of Ca²⁺ via the uniporter measured under a wide range of experimental conditions. The model is derived assuming a multi-state catalytic binding and Eyring's free-energy barrier theory-based transformation mechanisms associated with the carrier-mediated facilitated transport and electrodiffusion. The model is a great improvement over the previous theoretical models of mitochondrial Ca²⁺ uniporter in the literature in that it is thermodynamically balanced and matches a large number of independently published data sets on mitochondrial Ca²⁺ uptake. This theoretical model will be critical in developing mechanistic, integrated models of mitochondrial Ca²⁺ handling and bioenergetics which can be helpful in understanding the mechanisms by which Ca²⁺ plays a role in mediating signaling pathways and modulating mitochondrial energy metabolism.