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21 (24): 6744-6754

Copyright © 2002 by the European Molecular Biology Organization.

Store-operated Ca2+ entry depends on mitochondrial Ca2+ uptake

Maike D. Glitsch, Daniel Bakowski, and Anant B. Parekh1

Department of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, UK 1 Corresponding author e-mail: anant.parekh{at}physiol.ox.ac.uk

Abstract: Store-operated Ca2+ channels, which are activated by the emptying of intracellular Ca2+ stores, provide one major route for Ca2+ influx. Under physiological conditions of weak intracellular Ca2+ buffering, the ubiquitous Ca2+ releasing messenger InsP3 usually fails to activate any store-operated Ca2+ entry unless mitochondria are maintained in an energized state. Mitochondria rapidly take up Ca2+ that has been released by InsP3, enabling stores to empty sufficiently for store-operated channels to activate. Here, we report a novel role for mitochondria in regulating store-operated channels under physiological conditions. Mitochondrial depolarization suppresses store-operated Ca2+ influx independently of how stores are depleted. This role for mitochondria is unrelated to their actions on promoting InsP3-sensitive store depletion, can be distinguished from Ca2+-dependent inactivation of the store-operated channels and does not involve changes in intracellular ATP, oxidants, cytosolic acidification, nitric oxide or the permeability transition pore, but is suppressed when mitochondrial Ca2+ uptake is impaired. Our results suggest that mitochondria may have a more fundamental role in regulating store-operated influx and raise the possibility of bidirectional Ca2+-dependent crosstalk between mitochondria and store-operated Ca2+ channels.

Key Words: Keywords: Ca2+ influx/mitochondria/store-operated Ca2+ channels

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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882