Mathematical Characterization of the Inhibitory Effect of Mg 2+ on the Kinetics of Mitochondrial Ca 2+ Uniporter

Ca 2+ is a key regulatory ion and changes in mitochondrial Ca 2+ homeostasis can lead to cellular dysfunction and apoptosis. Ca 2+ is transported into respiring mitochondria via Ca 2+ uniporter, which is inhibited by Mg 2+ . In spite of a large number of experimental studies, the kinetic mechanism associated with the Ca 2+ transport and kinetic mechanism of Mg 2+ inhibition of the uniporter function is not clear. To gain a quantitative understanding of the effect of Mg 2+ on mitochondrial Ca 2+ regulation, we developed a biophysically‐based kinetic model of Ca 2+ uniporter on the basis of its kinetic properties and a presumed mechanism of Mg 2+ inhibition of the uniporter function. The model is extended from our previous model of Ca 2+ uniporter (Dash et al, Biophys J 96: 1318–1332, 2009) which is based on a multi‐state catalytic binding mechanism for carrier‐mediated transport and Eyring's free energy barrier theory for transformation. The model satisfactorily describes the available data on the kinetics of Ca 2+ uniporter and appropriately depicts the inhibitory effect of Mg 2+ on the uniporter function, in which Ca 2+ uptake is hyperbolic in the absence of Mg 2+ and sigmoid in the presence of Mg 2+ . This model can be useful for developing mechanistic models of mitochondrial bioenergetics and Ca 2+ handling to understand the mechanisms by which Ca 2+ plays a role in mediating signaling pathways and modulating energy metabolism.