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This Article Full Text Full Text (PDF) All Versions of this Article: 577/3/769    most recent jphysiol.2006.120584v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saks, V. Articles by Wallimann, T. Search for Related Content PubMed PubMed Citation Articles by Saks, V. Articles by Wallimann, T. Related Collections Review articles

¹ Laboratory of Bioenergetics, INSERM E221, Joseph Fourier University, Grenoble, France
² Laboratory of Bioenergetics, National Institute of Chemical and Biological Physics, Tallinn, Estonia
³ Institute of Cell Biology, ETH Zurich, Hönggerberg HPM, CH-8093 Zurich, Switzerland

This review re-evaluates regulatory aspects of substrate supply in heart. In aerobic heart, the preferred substrates are always free fatty acids, and workload-induced increase in their oxidation is observed at unchanged global levels of ATP, phosphocreatine and AMP. Here, we evaluate the mechanisms of regulation of substrate supply for mitochondrial respiration in muscle cells, and show that a system approach is useful also for revealing mechanisms of feedback signalling within the network of substrate oxidation and particularly for explaining the role of malonyl-CoA in regulation of fatty acid oxidation in cardiac muscle. This approach shows that a key regulator of fatty acid oxidation is the energy demand. Alterations in malonyl-CoA would not be the reason for, but rather the consequence of, the increased fatty acid oxidation at elevated workloads, when the level of acetyl-CoA decreases due to shifts in the kinetics of the Krebs cycle. This would make malonyl-CoA a feedback regulator that allows acyl-CoA entry into mitochondrial matrix space only when it is needed. Regulation of malonyl-CoA levels by AMPK does not seem to work as a master on–off switch, but rather as a modulator of fatty acid import.

(Received 6 September 2006; accepted after revision 25 September 2006; first published online 28 September 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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