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Published 18 December 2006. doi:10.1083/jcb.200608073
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 6, 901-911
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Article

Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels



György Szabadkai1, Katiuscia Bianchi1, Péter Várnai3, Diego De Stefani1, Mariusz R. Wieckowski1,4, Dario Cavagna1, Anikó I. Nagy3, Tamás Balla2, and Rosario Rizzuto1

1 Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, Emilia Romagna Laboratory for Genomics and Biotechnology, University of Ferrara, Ferrara 44100, Italy
2 Endocrinology and Reproduction Research Branch, National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
3 Department of Physiology, Semmelweis University, Faculty of Medicine, Budapest, 1081 Hungary
4 Department of Cellular Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur 3, Warsaw, 02-093, Poland

Correspondence to Rosario Rizzuto: rzr{at}unife.it

The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca2+, and cell death signaling between the endoplasmic reticulum (ER) and mitochondrial networks. We demonstrate that VDAC1 is physically linked to the endoplasmic reticulum Ca2+-release channel inositol 1,4,5-trisphosphate receptor (IP3R) through the molecular chaperone glucose-regulated protein 75 (grp75). Functional interaction between the channels was shown by the recombinant expression of the ligand-binding domain of the IP3R on the ER or mitochondrial surface, which directly enhanced Ca2+ accumulation in mitochondria. Knockdown of grp75 abolished the stimulatory effect, highlighting chaperone-mediated conformational coupling between the IP3R and the mitochondrial Ca2+ uptake machinery. Because organelle Ca2+ homeostasis influences fundamentally cellular functions and death signaling, the central location of grp75 may represent an important control point of cell fate and pathogenesis.

G. Szabadkai, K. Bianchi, and P. Várnai contributed equally to this paper.

Abbreviations used in this paper: grp, glucose-regulated protein; IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor; KRB, Krebs-Ringer bicarbonate; MAM, mitochondria-associated membrane; OMM, outer mitochondrial membrane; SERCA, sarcoplasmic reticulum Ca2+ ATPase; tBHQ, tert-butyl-benzohydroquinone; VDAC, voltage-dependent anion channel.


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