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Topical Review |
1 Structural and Quantitative Bioenergetics Research Group, Laboratory of Bioenergetics, INSERM E221, Joseph Fourier University Grenoble, France
2 Laboratory of Bioenergetics, National Institute of Chemical and Biological Physics, Tallinn, Estonia
3 Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Expermental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA
4 Institute of Cell Biology, Swiss Federal Institute of Technology (ETH), Hönggerberg HPM, CH-8093 Zürich, Switzerland
5 INSERM U446, Faculté de Pharmacie, Université Paris-Sud, 92296 Châtenay-Malabry, France
The fundamental principle of cardiac behaviour is described by the Frank-Starling law relating force of contraction during systole with end-diastolic volume. While both work and respiration rates increase linearly with imposed load, the basis of mechano-energetic coupling in heart muscle has remained a long-standing enigma. Here, we highlight advances made in understanding of complex cellular and molecular mechanisms that orchestrate coupling of mitochondrial oxidative phosphorylation with ATP utilization for muscle contraction. Cardiac system bioenergetics critically depends on an interrelated metabolic infrastructure regulating mitochondrial respiration and energy fluxes throughout cellular compartments. The data reviewed indicate the significance of two interrelated systems regulating mitochondrial respiration and energy fluxes in cells: (1) the creatine kinase, adenylate kinase and glycolytic pathways that communicate flux changes generated by cellular ATPases within structurally organized enzymatic modules and networks; and (2) a secondary system based on mitochondrial participation in cellular calcium cycle, which adjusts substrate oxidation and energy-transducing processes to meet increasing cellular energy demands. By conveying energetic signals to metabolic sensors, coupled phosphotransfer reactions provide a high-fidelity regulation of the excitation–contraction cycle. Such integration of energetics with calcium signalling systems provides the basis for ‘metabolic pacing’, synchronizing the cellular electrical and mechanical activities with energy supply processes.
(Received 6 November 2005;
accepted after revision 12 January 2006;
first published online 12 January 2006)
Corresponding author V. A. Saks: Laboratory of Bioenergetics, Joseph Fourier University, 2280, Rue de la Piscine, BP53X -38041, Grenoble Cedex 9, France. Email: valdur.saks{at}ujf-grenoble.fr
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