Characterization of Mg2+ Inhibition of Mitochondrial Ca2+ Uptake by a Mechanistic Model of Mitochondrial Ca2+ Uniporter

Abstract

Ca2+ is an important regulatory ion and alteration of mitochondrial Ca2+ homeostasis can lead to cellular dysfunction and apoptosis. Ca2+ is transported into respiring mitochondria via the Ca2+ uniporter, which is known to be inhibited by Mg2+. This uniporter-mediated mitochondrial Ca2+ transport is also shown to be influenced by inorganic phosphate (Pi). Despite a large number of experimental studies, the kinetic mechanisms associated with the Mg2+ inhibition and Pi regulation of the uniporter function are not well established. To gain a quantitative understanding of the effects of Mg2+ and Pi on the uniporter function, we developed here a mathematical model based on known kinetic properties of the uniporter and presumed Mg2+ inhibition and Pi regulation mechanisms. The model is extended from our previous model of the uniporter that is based on a multistate catalytic binding and interconversion mechanism and Eyring's free energy barrier theory for interconversion. The model satisfactorily describes a wide variety of experimental data sets on the kinetics of mitochondrial Ca2+ uptake. The model also appropriately depicts the inhibitory effect of Mg2+ on the uniporter function, in which Ca2+ uptake is hyperbolic in the absence of Mg2+ and sigmoid in the presence of Mg2+. The model suggests a mixed-type inhibition mechanism for Mg2+ inhibition of the uniporter function. This model is critical for building mechanistic models of mitochondrial bioenergetics and Ca2+ handling to understand the mechanisms by which Ca2+ mediates signaling pathways and modulates energy metabolism.