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J. Biol. Chem., Vol. 281, Issue 38, 28058-28067, September 22, 2006

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ATP Regulation in Adult Rat Cardiomyocytes

TIME-RESOLVED DECODING OF RAPID MITOCHONDRIAL CALCIUM SPIKING IMAGED WITH TARGETED PHOTOPROTEINS^*

Christopher J. Bell, Nicholas A. Bright^¶, Guy A. Rutter^||**1, and Elinor J. Griffiths²

From the Bristol Heart Institute, ^||Henry Wellcome Laboratories for Integrated Cell Signalling, the Department of Biochemistry, University of Bristol, Bristol BS8 1TD, the ^**Department of Cell Biology, Division of Medicine, Sir Alexander Fleming Building, Imperial College, Exhibition Road, London SW7 2AZ, and ^¶Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2XY, United Kingdom

The mechanisms that enable the heart to rapidly increase ATP supply in line with increased demand have not been fully elucidated. Here we used an adenoviral system to express the photoproteins luciferase and aequorin, targeted to the mitochondria or cytosol of adult cardiomyocytes, to investigate the interrelationship between ATP and Ca²⁺ in these compartments. In neither compartment were changes in free [ATP] observed upon increased workload (addition of isoproterenol) in myocytes that were already beating. However, when myocytes were stimulated to beat rapidly from rest, in the presence of isoproterenol, a significant but transient drop in mitochondrial [ATP] ([ATP]_m) occurred (on average to 10% of the initial signal). Corresponding changes in cytosolic [ATP] ([ATP]_c) were much smaller (<5%), indicating that [ATP]_c was effectively buffered in this compartment. Although mitochondrial [Ca²⁺] ([Ca²⁺]_m) is an important regulator of respiratory chain activity and ATP production in other cells, the kinetics of mitochondrial Ca²⁺ transport are controversial. Parallel experiments in cells expressing mitochondrial aequorin showed that the drop in [ATP]_m occurred over the same time scale as average [Ca²⁺]_m was increasing. Conversely, in the absence or presence of isoproterenol, clear beat-to-beat peaks in [Ca²⁺]_m were observed at 0.9 or 1.3 µM, respectively, concentrations similar to those observed in the cytosol. These results suggest that mitochondrial Ca²⁺ transients occur during the contractile cycle and are translated into a time-averaged increase in mitochondrial ATP production that keeps pace with increased cytosolic demand.

Received for publication, May 11, 2006 , and in revised form, July 10, 2006.

^* This work was supported by a British Heart Foundation project grant (to E. J. G. and G. A. R.) and a Wellcome Trust programme grant (to G. A. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures, supplemental Results, and supplemental Refs. 1–3.

¹ A Wellcome Trust research leave fellow.

² To whom correspondence should be addressed: Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, UK, BS8 1TD. Tel.: 117-9287502; Fax: 117-9288274; E-mail: Elinor.Griffiths{at}bristol.ac.uk.

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