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Characterization of Membrane Potential Dependency of Mitochondrial Ca2+ Uptake by an Improved Biophysical Model of Mitochondrial Ca2+ Uniporter

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  • Ranjan K Pradhan
  • Feng Qi
  • Daniel A Beard
  • Ranjan K Dash

Abstract

Mitochondrial Ca2+ uniporter is the primary influx pathway for Ca2+ into respiring mitochondria, and hence plays a key role in mitochondrial Ca2+ homeostasis. Though the mechanism of extra-matrix Ca2+ dependency of mitochondrial Ca2+ uptake has been well characterized both experimentally and mathematically, the mechanism of membrane potential (ΔΨ) dependency of mitochondrial Ca2+ uptake has not been completely characterized. In this paper, we perform a quantitative reevaluation of a previous biophysical model of mitochondrial Ca2+ uniporter that characterized the possible mechanism of ΔΨ dependency of mitochondrial Ca2+ uptake. Based on a model simulation analysis, we show that model predictions with a variant assumption (Case 2: external and internal Ca2+ binding constants for the uniporter are distinct), that provides the best possible description of the ΔΨ dependency, are highly sensitive to variation in matrix [Ca2+], indicating limitations in the variant assumption (Case 2) in providing physiologically plausible description of the observed ΔΨ dependency. This sensitivity is attributed to negative estimate of a biophysical parameter that characterizes binding of internal Ca2+ to the uniporter. Reparameterization of the model with additional nonnengativity constraints on the biophysical parameters showed that the two variant assumptions (Case 1 and Case 2) are indistinguishable, indicating that the external and internal Ca2+ binding constants for the uniporter may be equal (Case 1). The model predictions in this case are insensitive to variation in matrix [Ca2+] but do not match the ΔΨ dependent data in the domain ΔΨ≤120 mV. To effectively characterize this ΔΨ dependency, we reformulate the ΔΨ dependencies of the rate constants of Ca2+ translocation via the uniporter by exclusively redefining the biophysical parameters associated with the free-energy barrier of Ca2+ translocation based on a generalized, non-linear Goldman-Hodgkin-Katz formulation. This alternate uniporter model has all the characteristics of the previous uniporter model and is also able to characterize the possible mechanisms of both the extra-matrix Ca2+ and ΔΨ dependencies of mitochondrial Ca2+ uptake. In addition, the model is insensitive to variation in matrix [Ca2+], predicting relatively stable physiological operation. The model is critical in developing mechanistic, integrated models of mitochondrial bioenergetics and Ca2+ handling.

Suggested Citation

  • Ranjan K Pradhan & Feng Qi & Daniel A Beard & Ranjan K Dash, 2010. "Characterization of Membrane Potential Dependency of Mitochondrial Ca2+ Uptake by an Improved Biophysical Model of Mitochondrial Ca2+ Uniporter," PLOS ONE, Public Library of Science, vol. 5(10), pages 1-10, October.
  • Handle: RePEc:plo:pone00:0013278
    DOI: 10.1371/journal.pone.0013278
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    References listed on IDEAS

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    1. Yuriy Kirichok & Grigory Krapivinsky & David E. Clapham, 2004. "The mitochondrial calcium uniporter is a highly selective ion channel," Nature, Nature, vol. 427(6972), pages 360-364, January.
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