Modeling the calcium sequestration system in isolated guinea pig cardiac mitochondria

• Published in: Journal of bioenergetics and biomembranes Vol. 45; no. 3; pp. 177 - 188
• Main Authors: Bazil, Jason N., Blomeyer, Christoph A., Pradhan, Ranjan K., Camara, Amadou K. S., Dash, Ranjan K.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-06-2013; Springer Nature B.V
• Subjects: Animal Anatomy; Animal Biochemistry; Animals; Biochemistry; Bioenergetics; Bioorganic Chemistry; Calcium; Calcium - chemistry; Calcium - metabolism; Calcium phosphates; Calcium sequestration; Chemistry; Chemistry and Materials Science; Guinea Pigs; Histology; Mathematical models; Mitochondria; Mitochondria, Heart - chemistry; Mitochondria, Heart - metabolism; Models, Biological; Morphology; Organic Chemistry; Rodents; Ruthenium; Sodium - chemistry; Sodium - metabolism; Sodium chloride; Mitochondria; Calcium; Bioenergetics; Mathematical model; Buffering; Sequestration
• ISSN: 0145-479X; 1573-6881
• DOI: 10.1007/s10863-012-9488-2

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.