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

Abstract

Ca 2+ transport through mitochondrial Ca 2+ uniporter is the primary Ca 2+ uptake mechanism in respiring mitochondria. Thus, the uniporter plays a key role in regulating mitochondrial Ca 2+. Despite the importance of mitochondrial Ca 2+ 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 Ca 2+ transport into mitochondria are still not well understood. In this study, based on available experimental data on the kinetics of Ca 2+ 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 Ca 2+ 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 Ca 2+ uniporter in the literature in that it is thermodynamically balanced and matches a large number of independently published data sets on mitochondrial Ca 2+ uptake. This theoretical model will be critical in developing mechanistic, integrated models of mitochondrial Ca 2+ handling and bioenergetics which can be helpful in understanding the mechanisms by which Ca 2+ plays a role in mediating signaling pathways and modulating mitochondrial energy metabolism.