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Calreticulin differentially modulates calcium uptake and release in the endoplasmic reticulum and mitochondria

Nakamura, Kimitoshi
Published in The Journal of biological chemistry. 2002, vol. 277, no. 48, p. 46696-705
Abstract To study the role of calreticulin in Ca(2+) homeostasis and apoptosis, we generated cells inducible for full-length or truncated calreticulin and measured Ca(2+) signals within the cytosol, the endoplasmic reticulum (ER), and mitochondria with "cameleon" indicators. Induction of calreticulin increased the free Ca(2+) concentration within the ER lumen, [Ca(2+)](ER), from 306 +/- 31 to 595 +/- 53 microm, and doubled the rate of ER refilling. [Ca(2+)](ER) remained elevated in the presence of thapsigargin, an inhibitor of SERCA-type Ca(2+) ATPases. Under these conditions, store-operated Ca(2+) influx appeared inhibited but could be reactivated by decreasing [Ca(2+)](ER) with the low affinity Ca(2+) chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine. In contrast, [Ca(2+)](ER) decreased much faster during stimulation with carbachol. The larger ER release was associated with a larger cytosolic Ca(2+) response and, surprisingly, with a shorter mitochondrial Ca(2+) response. The reduced mitochondrial signal was not associated with visible morphological alterations of mitochondria or with disruption of the contacts between mitochondria and the ER but correlated with a reduced mitochondrial membrane potential. Altered ER and mitochondrial Ca(2+) responses were also observed in cells expressing an N-truncated calreticulin but not in cells overexpressing calnexin, a P-domain containing chaperone, indicating that the effects were mediated by the unique C-domain of calreticulin. In conclusion, calreticulin overexpression increases Ca(2+) fluxes across the ER but decreases mitochondrial Ca(2+) and membrane potential. The increased Ca(2+) turnover between the two organelles might damage mitochondria, accounting for the increased susceptibility of cells expressing high levels of calreticulin to apoptotic stimuli.
Keywords ApoptosisBlotting, WesternCalcium/metabolismCalreticulin/physiologyCell LineCytosol/metabolismEndoplasmic Reticulum/metabolismHomeostasis/physiologyHumansImmunohistochemistryMembrane PotentialsMitochondria/metabolism
PMID: 12324449
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ARNAUDEAU, Serge et al. Calreticulin differentially modulates calcium uptake and release in the endoplasmic reticulum and mitochondria. In: The Journal of biological chemistry, 2002, vol. 277, n° 48, p. 46696-705. doi: 10.1074/jbc.M202395200 https://archive-ouverte.unige.ch/unige:30404

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Deposited on : 2013-10-15

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