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Sci. STKE, 13 January 2004
Vol. 2004, Issue 215, p. re1
[DOI: 10.1126/stke.2152004re1]


Flirting in Little Space: The ER/Mitochondria Ca2+ Liaison

Rosario Rizzuto1, Michael R. Duchen2, and Tullio Pozzan3,4*

1Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, Italy.
2Department of Physiology, University College London, UK.
3Department of Biomedical Sciences and CNR Institute of Neurosciences, University of Padua, Italy.
4Venetian Institute of Molecular Medicine, Padua, Italy.

Abstract: Mitochondria have long been known to accumulate Ca2+; the apparent inconsistency between the low affinity of mitochondrial Ca2+ uptake mechanisms, the low concentration of global Ca2+ signals observed in cytoplasm, and the efficiency in intact cells of mitochondrial Ca2+ uptake led to the formulation of the "hotspot hypothesis." This hypothesis proposes that mitochondria preferentially accumulate Ca2+ at microdomains of elevated Ca2+ concentration ([Ca2+]) that exist near endoplasmic reticulum (ER) Ca2+ release sites and other Ca2+ channels. Physiological Ca2+ signals may affect mitochondrial function--both by stimulating key metabolic enzymes and, under some conditions, by promoting apoptosis. Mitochondria in turn may affect both Ca2+ release from the ER and capacitative Ca2+ entry across the plasma membrane, thereby shaping the size and duration of the intracellular Ca2+ signal. Interactions between mitochondria and the ER are critically dependent on the spatial localization of mitochondria within the cell. The molecular mechanisms that define the organization of mitochondria with regard to the ER and other Ca2+ sources, and the extent to which mitochondrial function varies among different cell types, are open questions whose answers remain to be determined.

*Corresponding author. E-mail: tullio.pozzan{at}

Citation: R. Rizzuto, M. R. Duchen, T. Pozzan, Flirting in Little Space: The ER/Mitochondria Ca2+ Liaison. Sci. STKE 2004, re1 (2004).

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J. Biol. Chem. 288, 11122-11134
   Abstract »    Full Text »    PDF »
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X. Lu, K. S. Ginsburg, S. Kettlewell, J. Bossuyt, G. L. Smith, and D. M. Bers (2013)
Circ. Res. 112, 424-431
   Abstract »    Full Text »    PDF »
Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals.
B. S. Kilpatrick, E. R. Eden, A. H. Schapira, C. E. Futter, and S. Patel (2013)
J. Cell Sci. 126, 60-66
   Abstract »    Full Text »    PDF »
Virtual nanoscopy: Generation of ultra-large high resolution electron microscopy maps.
F. G. A. Faas, M. C. Avramut, B. M. van den Berg, A. M. Mommaas, A. J. Koster, and R. B. G. Ravelli (2012)
J. Cell Biol. 198, 457-469
   Abstract »    Full Text »    PDF »
CD4+ T-cell synapses involve multiple distinct stages.
H. Ueda, M. K. Morphew, J. R. McIntosh, and M. M. Davis (2011)
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 286, 28444-28455
   Abstract »    Full Text »    PDF »
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G. Sutendra, P. Dromparis, P. Wright, S. Bonnet, A. Haromy, Z. Hao, M. S. McMurtry, M. Michalak, J. E. Vance, W. C. Sessa, et al. (2011)
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J. L. Greenstein and R. L. Winslow (2011)
Circ. Res. 108, 70-84
   Abstract »    Full Text »    PDF »
Biology of Endoplasmic Reticulum Stress in the Heart.
J. Groenendyk, P. K. Sreenivasaiah, D. H. Kim, L. B. Agellon, and M. Michalak (2010)
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   Abstract »    Full Text »    PDF »
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P. Bozidis, C. D. Williamson, D. S. Wong, and A. M. Colberg-Poley (2010)
J. Virol. 84, 7898-7903
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A. Arachiche, D. Kerbiriou-Nabias, I. Garcin, T. Letellier, and J. Dachary-Prigent (2009)
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X. Wang, R. P. Rao, T. Kosakowska-Cholody, M. A. Masood, E. Southon, H. Zhang, C. Berthet, K. Nagashim, T. K. Veenstra, L. Tessarollo, et al. (2009)
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U. Schenk, A. M. Westendorf, E. Radaelli, A. Casati, M. Ferro, M. Fumagalli, C. Verderio, J. Buer, E. Scanziani, and F. Grassi (2008)
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T. Szado, V. Vanderheyden, J. B. Parys, H. De Smedt, K. Rietdorf, L. Kotelevets, E. Chastre, F. Khan, U. Landegren, O. Soderberg, et al. (2008)
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