Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter.

Mitochondrial Ca(2+) uniporter is the primary influx pathway for Ca(2+) into respiring mitochondria, and hence plays a key role in mitochondrial Ca(2+) homeostasis. Though the mechanism of extra-matrix Ca(2+) dependency of mitochondrial Ca(2+) uptake has been well characterized both experimentally a...

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Autores principales:	Ranjan K Pradhan, Feng Qi, Daniel A Beard, Ranjan K Dash
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bd9fee69923e409e982b032bd156e20b
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spelling	oai:doaj.org-article:bd9fee69923e409e982b032bd156e20b2021-11-18T07:03:33ZCharacterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter.1932-620310.1371/journal.pone.0013278https://doaj.org/article/bd9fee69923e409e982b032bd156e20b2010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20949039/?tool=EBIhttps://doaj.org/toc/1932-6203Mitochondrial Ca(2+) uniporter is the primary influx pathway for Ca(2+) into respiring mitochondria, and hence plays a key role in mitochondrial Ca(2+) homeostasis. Though the mechanism of extra-matrix Ca(2+) dependency of mitochondrial Ca(2+) uptake has been well characterized both experimentally and mathematically, the mechanism of membrane potential (ΔΨ) dependency of mitochondrial Ca(2+) uptake has not been completely characterized. In this paper, we perform a quantitative reevaluation of a previous biophysical model of mitochondrial Ca(2+) uniporter that characterized the possible mechanism of ΔΨ dependency of mitochondrial Ca(2+) uptake. Based on a model simulation analysis, we show that model predictions with a variant assumption (Case 2: external and internal Ca(2+) binding constants for the uniporter are distinct), that provides the best possible description of the ΔΨ dependency, are highly sensitive to variation in matrix [Ca(2+)], 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 Ca(2+) 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 Ca(2+) binding constants for the uniporter may be equal (Case 1). The model predictions in this case are insensitive to variation in matrix [Ca(2+)] 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 Ca(2+) translocation via the uniporter by exclusively redefining the biophysical parameters associated with the free-energy barrier of Ca(2+) 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 Ca(2+) and ΔΨ dependencies of mitochondrial Ca(2+) uptake. In addition, the model is insensitive to variation in matrix [Ca(2+)], predicting relatively stable physiological operation. The model is critical in developing mechanistic, integrated models of mitochondrial bioenergetics and Ca(2+) handling.Ranjan K PradhanFeng QiDaniel A BeardRanjan K DashPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10, p e13278 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ranjan K Pradhan Feng Qi Daniel A Beard Ranjan K Dash Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter.
description	Mitochondrial Ca(2+) uniporter is the primary influx pathway for Ca(2+) into respiring mitochondria, and hence plays a key role in mitochondrial Ca(2+) homeostasis. Though the mechanism of extra-matrix Ca(2+) dependency of mitochondrial Ca(2+) uptake has been well characterized both experimentally and mathematically, the mechanism of membrane potential (ΔΨ) dependency of mitochondrial Ca(2+) uptake has not been completely characterized. In this paper, we perform a quantitative reevaluation of a previous biophysical model of mitochondrial Ca(2+) uniporter that characterized the possible mechanism of ΔΨ dependency of mitochondrial Ca(2+) uptake. Based on a model simulation analysis, we show that model predictions with a variant assumption (Case 2: external and internal Ca(2+) binding constants for the uniporter are distinct), that provides the best possible description of the ΔΨ dependency, are highly sensitive to variation in matrix [Ca(2+)], 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 Ca(2+) 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 Ca(2+) binding constants for the uniporter may be equal (Case 1). The model predictions in this case are insensitive to variation in matrix [Ca(2+)] 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 Ca(2+) translocation via the uniporter by exclusively redefining the biophysical parameters associated with the free-energy barrier of Ca(2+) 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 Ca(2+) and ΔΨ dependencies of mitochondrial Ca(2+) uptake. In addition, the model is insensitive to variation in matrix [Ca(2+)], predicting relatively stable physiological operation. The model is critical in developing mechanistic, integrated models of mitochondrial bioenergetics and Ca(2+) handling.
format	article
author	Ranjan K Pradhan Feng Qi Daniel A Beard Ranjan K Dash
author_facet	Ranjan K Pradhan Feng Qi Daniel A Beard Ranjan K Dash
author_sort	Ranjan K Pradhan
title	Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter.
title_short	Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter.
title_full	Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter.
title_fullStr	Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter.
title_full_unstemmed	Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter.
title_sort	characterization of membrane potential dependency of mitochondrial ca2+ uptake by an improved biophysical model of mitochondrial ca2+ uniporter.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/bd9fee69923e409e982b032bd156e20b
work_keys_str_mv	AT ranjankpradhan characterizationofmembranepotentialdependencyofmitochondrialca2uptakebyanimprovedbiophysicalmodelofmitochondrialca2uniporter AT fengqi characterizationofmembranepotentialdependencyofmitochondrialca2uptakebyanimprovedbiophysicalmodelofmitochondrialca2uniporter AT danielabeard characterizationofmembranepotentialdependencyofmitochondrialca2uptakebyanimprovedbiophysicalmodelofmitochondrialca2uniporter AT ranjankdash characterizationofmembranepotentialdependencyofmitochondrialca2uptakebyanimprovedbiophysicalmodelofmitochondrialca2uniporter
_version_	1718424004537090048

Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter.

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