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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.

SUBMITTER: Bazil JN

PROVIDER: S-EPMC3615037 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Modeling the calcium sequestration system in isolated guinea pig cardiac mitochondria.

Bazil Jason N JN Blomeyer Christoph A CA Pradhan Ranjan K RK Camara Amadou K S AK Dash Ranjan K RK

Journal of bioenergetics and biomembranes 20121122 3

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 ...[more]

PMID: 23180139

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Project description:Ca(2+) plays a central role in energy supply and demand matching in cardiomyocytes by transmitting changes in excitation-contraction coupling to mitochondrial oxidative phosphorylation. Matrix Ca(2+) is controlled primarily by the mitochondrial Ca(2+) uniporter and the mitochondrial Na(+)/Ca(2+) exchanger, influencing NADH production through Ca(2+)-sensitive dehydrogenases in the Krebs cycle. In addition to the well-accepted role of the Ca(2+)-triggered mitochondrial permeability transition pore in cell death, it has been proposed that the permeability transition pore might also contribute to physiological mitochondrial Ca(2+) release. Here we selectively measure Ca(2+) influx rate through the mitochondrial Ca(2+) uniporter and Ca(2+) efflux rates through Na(+)-dependent and Na(+)-independent pathways in isolated guinea pig heart mitochondria in the presence or absence of inhibitors of mitochondrial Na(+)/Ca(2+) exchanger (CGP 37157) or the permeability transition pore (cyclosporine A). cyclosporine A suppressed the negative bioenergetic consequences (??(m) loss, Ca(2+) release, NADH oxidation, swelling) of high extramitochondrial Ca(2+) additions, allowing mitochondria to tolerate total mitochondrial Ca(2+) loads of >400nmol/mg protein. For Ca(2+) pulses up to 15?M, Na(+)-independent Ca(2+) efflux through the permeability transition pore accounted for ~5% of the total Ca(2+) efflux rate compared to that mediated by the mitochondrial Na(+)/Ca(2+) exchanger (in 5mM Na(+)). Unexpectedly, we also observed that cyclosporine A inhibited mitochondrial Na(+)/Ca(2+) exchanger-mediated Ca(2+) efflux at higher concentrations (IC(50)=2?M) than those required to inhibit the permeability transition pore, with a maximal inhibition of ~40% at 10?M cyclosporine A, while having no effect on the mitochondrial Ca(2+) uniporter. The results suggest a possible alternative mechanism by which cyclosporine A could affect mitochondrial Ca(2+) load in cardiomyocytes, potentially explaining the paradoxical toxic effects of cyclosporine A at high concentrations. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.

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Dataset Information

Modeling the calcium sequestration system in isolated guinea pig cardiac mitochondria.

Publications

Modeling the calcium sequestration system in isolated guinea pig cardiac mitochondria.

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