Store-operated Ca2+ entry depends on mitochondrial Ca2+ uptake.
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.
Glitsch
Maike D
MD
Department of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
Bakowski
Daniel
D
Parekh
Anant B
AB
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000378:metabolism; D004533:Egtazic Acid / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D010100:Oxygen / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors
D000975:Antioxidants; D015220:Calcium Channels; D012430:Ruthenium Red; C085029:adenophostin A; D009569:Nitric Oxide; D004533:Egtazic Acid; D019284:Thapsigargin; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D000241:Adenosine; D010100:Oxygen; D002118:Calcium