title: Release of mitochondrial Ca2+ via the permeability transition activates endoplasmic reticulum Ca2+ uptake.
abstract: Regulatory interactions between the endoplasmic reticulum (ER) and the mitochondria in the control of intracellular free Ca2+ concentration ([Ca2+]I), may be of importance in the control of many cell functions, and particularly those involved in initiating cell death. We used targeted Ca2+ sensors (cameleons) to investigate the movement of Ca2+ between the ER and mitochondria of intact cells and focused on the role of the mitochondrial permeability transition (MPT) in this interaction. We hypothesized that release of Ca2+ from mitochondria in response to a known MPT agonist (atractyloside) would cause release of ER Ca2+, perpetuating cellular Ca2+ overload, and cell death. Targeted cameleons (mitochondria and ER) were imaged with confocal microscopy 2-3 days following transient transfection of human embryonic kidney 293 cells. Opening of the MPT resulted in specific loss of mitochondrial Ca2+ (blocked by cyclosporin A), which was sequestered initially by ER. The ER subsequently released this Ca2+ load, leading to a global Ca2+ elevation, a response that was not observed when ER Ca2+-ATPases were blocked with cyclopiazonic acid. Thus, ER plays an important role in moderating changes in intracellular Ca2+ following MPT and may play a key role in cell death initiated by mitochondrial mechanisms.
authors.affiliation: Department of Physiology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: David N
authors.initials: DN
authors.lastname: Bowser
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.forename: Rekha G
authors.initials: RG
authors.lastname: Panchal
authors.forename: Megan L
authors.initials: ML
authors.lastname: Smart
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
mesh_terms: D001278:Atractyloside / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels / Q000819:agonists / Q000378:metabolism*; D017136:Ion Transport; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008954:Models, Biological
chemical_list: D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D001278:Atractyloside; D002118:Calcium