Modeling the calcium sequestration system in isolated guinea pig cardiac mitochondria

Under high Ca 2+ load conditions, Ca 2+ concentrations in the extra-mitochondrial and mitochondrial compartments do not display reciprocal dynamics. This is due to a paradoxical increase in the mitochondrial Ca 2+ buffering power as the Ca 2+ load increases. Here we develop and characterize a mechanism of the mitochondrial Ca 2+ sequestration system using an experimental data set from isolated guinea pig cardiac mitochondria. The proposed mechanism elucidates this phenomenon and others in a mathematical framework and is integrated into a previously corroborated model of oxidative phosphorylation including the Na + /Ca 2+ cycle. The integrated model reproduces the Ca 2+ dynamics observed in both compartments of the isolated mitochondria respiring on pyruvate after a bolus of CaCl 2 followed by ruthenium red and a bolus of NaCl. The model reveals why changes in mitochondrial Ca 2+ concentration of Ca 2+ loaded mitochondria appear significantly mitigated relative to the corresponding extra-mitochondrial Ca 2+ concentration changes after Ca 2+ efflux is initiated. The integrated model was corroborated by simulating the set-point phenomenon. The computational results support the conclusion that the Ca 2+ sequestration system is composed of at least two classes of Ca 2+ buffers. The first class represents prototypical Ca 2+ buffering, and the second class encompasses the complex binding events associated with the formation of amorphous calcium phosphate. With the Ca 2+ sequestration system in mitochondria more precisely defined, computer simulations can aid in the development of innovative therapeutics aimed at addressing the myriad of complications that arise due to mitochondrial Ca 2+ overload.