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Analysis of cardiac mitochondrial Na+-Ca2+ exchanger kinetics with a biophysical model of mitochondrial Ca2+ handling suggests a 3:1 stoichiometry. J Physiol 2008 Jul 01;586(13):3267-85

Date

05/10/2008

Pubmed ID

18467367

Pubmed Central ID

PMC2538784

DOI

10.1113/jphysiol.2008.151977

Scopus ID

2-s2.0-47249162028   54 Citations

Abstract

Calcium is a key ion and is known to mediate signalling pathways between cytosol and mitochondria and modulate mitochondrial energy metabolism. To gain a quantitative, biophysical understanding of mitochondrial Ca(2+) regulation, we developed a thermodynamically balanced model of mitochondrial Ca(2+) handling and bioenergetics by integrating kinetic models of mitochondrial Ca(2+) uniporter (CU), Na(+)-Ca(2+) exchanger (NCE), and Na(+)-H(+) exchanger (NHE) into an existing computational model of mitochondrial oxidative phosphorylation. Kinetic flux expressions for the CU, NCE and NHE were developed and individually parameterized based on independent data sets on flux rates measured in purified mitochondria. While available data support a wide range of possible values for the overall activity of the CU in cardiac and liver mitochondria, even at the highest estimated values, the Ca(2+) current through the CU does not have a significant effect on mitochondrial membrane potential. This integrated model was then used to analyse additional data on the dynamics and steady-states of mitochondrial Ca(2+) governed by mitochondrial CU and NCE. Our analysis of the data on the time course of matrix free [Ca(2+)] in respiring mitochondria purified from rabbit heart with addition of different levels of Na(+) to the external buffer medium (with the CU blocked) with two separate models--one with a 2:1 stoichiometry and the other with a 3:1 stoichiometry for the NCE--supports the hypothesis that the NCE is electrogenic with a stoichiometry of 3:1. This hypothesis was further tested by simulating an additional independent data set on the steady-state variations of matrix free [Ca(2+)] with respect to the variations in external free [Ca(2+)] in purified respiring mitochondria from rat heart to show that only the 3:1 stoichiometry model predictions are consistent with the data. Based on these analyses, it is concluded that the mitochondrial NCE is electrogenic with a stoichiometry of 3:1.

Author List

Dash RK, Beard DA

Author

Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Calcium
Egtazic Acid
Mathematics
Mitochondria, Heart
Models, Biological
Protons
Reproducibility of Results
Sodium
Sodium-Calcium Exchanger
jenkins-FCD Prod-400 0f9a74600e4e79798f8fa6f545ea115f3dd948b2