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Store-operated Ca(2+) channels, which are activated by the emptying of intracellular Ca(2+) stores, provide one major route for Ca(2+) influx. Under physiological conditions of weak intracellular Ca(2+) buffering, the ubiquitous Ca(2+) releasing messenger InsP(3) usually fails to activate any store-operated Ca(2+) entry unless mitochondria are maintained in an energized state. Mitochondria rapidly take up Ca(2+) that has been released by InsP(3), 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 Ca(2+) influx independently of how stores are depleted. This role for mitochondria is unrelated to their actions on promoting InsP(3)-sensitive store depletion, can be distinguished from Ca(2+)-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 Ca(2+) 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 Ca(2+)-dependent crosstalk between mitochondria and store-operated Ca(2+) channels.

Type

Journal article

Journal

EMBO J

Publication Date

16/12/2002

Volume

21

Pages

6744 - 6754

Keywords

Adenosine, Adenosine Triphosphate, Animals, Antioxidants, Calcium, Calcium Channels, Cell Line, Tumor, Cyclosporine, Egtazic Acid, Hydrogen-Ion Concentration, Membrane Potentials, Mitochondria, Nitric Oxide, Oxygen, Patch-Clamp Techniques, Rats, Ruthenium Red, Thapsigargin, Time Factors