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 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.

Dynamic buffering of mitochondrial Ca2+ during Ca2+ uptake and Na+-induced Ca2+ release

“…Indeed, findings derived from this computational study (Bazil et al 2012) corroborate our experimental observations regarding the existence of a dynamic matrix Ca 2+ buffering system during variations in Ca 2+ uptake and release.…”

“…This indicates that the matrix Ca 2+ buffering power depends on the amount of Ca 2+ taken up. This notion of dynamic matrix Ca 2+ buffering is supported by our companion paper (Bazil et al 2012), in which our experimental data on NCE dynamics were computationally analyzed to estimate the matrix Ca 2+ buffering power (β Ca,m ) and to characterize the mitochondrial sequestration system. A basic prerequisite for quantification of the Ca 2+ buffering power is the data on total and free [Ca 2+ ] in the extra-matrix and matrix compartments.…”

“…To our knowledge, these salient observations of dynamic Ca 2+ uptake and release have not been previously described in such a detailed and systematic manner. In addition, our data provided an opportunity to quantify the dynamic Ca 2+ buffering system of the matrix compartment under our experimental conditions using a computational approach (see companion paper (Bazil et al 2012)). Lastly, the observed activity of the CU in the presence of 40 μM CaCl 2 transiently influenced NADH, ΔΨ m , pH m and matrix volume (Fig.…”

“…These data were also utilized in our companion paper (Bazil et al 2012), which computationally characterized the dynamics of Ca 2+ uptake and release by the matrix Ca 2+ sequestration system. More importantly, the computations from our companion paper support our experimental findings regarding the dynamic Ca 2+ buffering power of the matrix compartment.…”

“…Our data on [Ca 2+ ] e and [Ca 2+ ] m during Ca 2+ uptake and Na + -induced Ca 2+ release were then utilized to quantify the mitochondrial Ca 2+ buffering system using a mathematical model (see our companion paper (Bazil et al 2012)). Indeed, findings derived from this computational study (Bazil et al 2012) corroborate our experimental observations regarding the existence of a dynamic matrix Ca 2+ buffering system during variations in Ca 2+ uptake and release.…”