Modeling the calcium sequestration system in isolated guinea pig cardiac mitochondria. J Bioenerg Biomembr 2013 Jun;45(3):177-88
Date
11/28/2012Pubmed ID
23180139Pubmed Central ID
PMC3615037DOI
10.1007/s10863-012-9488-2Scopus ID
2-s2.0-84878638876 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
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.
Author List
Bazil JN, Blomeyer CA, Pradhan RK, Camara AK, Dash RKAuthors
Amadou K. Camara PhD Professor in the Anesthesiology department at Medical College of WisconsinRanjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCalcium
Guinea Pigs
Mitochondria, Heart
Models, Biological
Sodium