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Biophysical Journal 87:696-713 (2004)
© 2004 The Biophysical Society

Analysis of Functional Coupling: Mitochondrial Creatine Kinase and Adenine Nucleotide Translocase

Marko Vendelin * {dagger}, Maris Lemba {dagger} and Valdur A. Saks * {ddagger}

* Laboratory of Fundamental and Applied Bioenergetics, Institut National de la Santé et de la Recherche Médicale E0221, Joseph Fourier University, Grenoble, France; {dagger} Institute of Cybernetics, Tallinn Technical University, Tallinn, Estonia; and {ddagger} Laboratory of Bioenergetics, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia

Correspondence: Address reprint requests to Marko Vendelin at his present address: Laboratory of Fundamental and Applied Bioenergetics, INSERM E0221, Université J. Fourier, BP 53, F-38041, Grenoble, France. Tel.: 372-620-4151; Fax: 372-620-4169; E-mail: markov{at}ioc.ee.

The mechanism of functional coupling between mitochondrial creatine kinase (MiCK) and adenine nucleotide translocase (ANT) in isolated heart mitochondria is analyzed. Two alternative mechanisms are studied: 1), dynamic compartmentation of ATP and ADP, which assumes the differences in concentrations of the substrates between intermembrane space and surrounding solution due to some diffusion restriction and 2), direct transfer of the substrates between MiCK and ANT. The mathematical models based on these possible mechanisms were composed and simulation results were compared with the available experimental data. The first model, based on a dynamic compartmentation mechanism, was not sufficient to reproduce the measured values of apparent dissociation constants of MiCK reaction coupled to oxidative phosphorylation. The second model, which assumes the direct transfer of substrates between MiCK and ANT, is shown to be in good agreement with experiments—i.e., the second model reproduced the measured constants and the estimated ADP flux, entering mitochondria after the MiCK reaction. This model is thermodynamically consistent, utilizing the free energy profiles of reactions. The analysis revealed the minimal changes in the free energy profile of the MiCK-ANT interaction required to reproduce the experimental data. A possible free energy profile of the coupled MiCK-ANT system is presented.




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