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Mitochondrial Ca2+ uptake requires sustained Ca2+ release from the endoplasmic reticulum

Szabadkai, G; Simoni, AM; Rizzuto, R; (2003) Mitochondrial Ca2+ uptake requires sustained Ca2+ release from the endoplasmic reticulum. J BIOL CHEM , 278 (17) 15153 - 15161. 10.1074/jbc.M300180200. Gold open access

Abstract

We analyzed the role of inositol 1,4,5-trisphosphate-induced Ca2+ release from the endoplasmic reticulum (ER) (i) in powering mitochondrial Ca2+ uptake and (ii) in maintaining a sustained elevation of cytosolic Ca2+ concentration ([Ca2+](c)). For this purpose, we expressed in HeLa cells aequorin-based Ca2+-sensitive probes targeted to different intracellular compartments and studied the effect of two agonists: histamine, acting on endogenous H-1 receptors, and glutamate, acting on co-transfected metabotropic glutamate receptor (mGluR1a), which rapidly inactivates through protein kinase C-dependent phosphorylation and thus causes transient inositol 1,4,5-trisphosphate production. Glutamate induced a transient [Ca2+](c) rise and drop in ER luminal [Ca2+] ([Ca2+](er)), and then the ER refilled with [Ca2+](c) at resting values. With histamine, [Ca2+](c) after the initial peak stabilized at a sustained plateau, and [Ca2+](er) decreased to a low steady-state value. In mitochondria, histamine evoked a much larger mitochondrial Ca2+ response than glutamate (similar to15 versus similar to65 muM). Protein kinase C inhibition, partly relieving mGluR1a desensitization, reestablished both the [Ca2+](c) plateau and the sustained ER Ca2+ release and markedly increased the mitochondrial Ca2+ response. Conversely, mitochondrial Ca2+ uptake evoked by histamine was drastically reduced by very transient (similar to2-s) agonist applications. These data indicate that efficient mitochondrial Ca2+ uptake depends on the preservation of high Ca2+ microdomains at the mouth of ER Ca2+ release sites close to mitochondria. This in turn depends on continuous Ca2+ release balanced by Ca2+ reuptake into the ER and maintained by Ca2+ influx from the extracellular space.

Type: Article
Title: Mitochondrial Ca2+ uptake requires sustained Ca2+ release from the endoplasmic reticulum
Open access status: An open access publication
DOI: 10.1074/jbc.M300180200
Keywords: PANCREATIC ACINAR-CELLS, PROTEIN-KINASE-C, INTACT-CELLS, CYTOPLASMIC CA2+, ENTRY PATHWAYS, SMOOTH-MUSCLE, CALCIUM-ENTRY, STORES, OSCILLATIONS, PHOSPHORYLATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/10767
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