title: Modeling the calcium sequestration system in isolated guinea pig cardiac mitochondria.
abstract: 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 CaCl2 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.
authors.affiliation: Biotechnology and Bioengineering Center and Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Bazil
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Blomeyer
authors.forename: Ranjan K
authors.initials: RK
authors.lastname: Pradhan
authors.forename: Amadou K S
authors.initials: AK
authors.lastname: Camara
authors.forename: Ranjan K
authors.initials: RK
authors.lastname: Dash
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D006168:Guinea Pigs; D008929:Mitochondria, Heart / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D012964:Sodium / Q000737:chemistry / Q000378:metabolism
chemical_list: D012964:Sodium; D002118:Calcium