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J. Cell Biol. 159 (4): 613-624

Copyright © 2002 by the Rockefeller University Press.


Article

Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria

Elena Rapizzi1,2, Paolo Pinton1, György Szabadkai1, Mariusz R. Wieckowski1, Grégoire Vandecasteele1, Geoff Baird3, Richard A. Tuft2, Kevin E. Fogarty2, and Rosario Rizzuto1

1 Department of Experimental and Diagnostic Medicine, Section of General Pathology, Telethon Center for Cell Imaging and Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Via Borsari 46, I-44100 Ferrara, Italy
2 Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA 01655
3 Howard Hughes Medical Institute and Department of Pharmacology, University of California, San Diego, CA 92093

Address correspondence to Rosario Rizzuto, Dept. Exp. Diagn. Med. Sect. Gen. Pathol., Via Borsari 46, I-44100 Ferrara, Italy. Tel.: 39-0532-291361. Fax: 39-0532-247278. E-mail: r.rizzuto{at}unife.it

Abstract: Although the physiological relevance of mitochondrial Ca2+ homeostasis is widely accepted, no information is yet available on the molecular identity of the proteins involved in this process. Here we analyzed the role of the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane in the transmission of Ca2+ signals between the ER and mitochondria by measuring cytosolic and organelle [Ca2+] with targeted aequorins and Ca2+-sensitive GFPs. In HeLa cells and skeletal myotubes, the transient expression of VDAC enhanced the amplitude of the agonist-dependent increases in mitochondrial matrix Ca2+ concentration by allowing the fast diffusion of Ca2+ from ER release sites to the inner mitochondrial membrane. Indeed, high speed imaging of mitochondrial and cytosolic [Ca2+] changes showed that the delay between the rises occurring in the two compartments is significantly shorter in VDAC-overexpressing cells. As to the functional consequences, VDAC-overexpressing cells are more susceptible to ceramide-induced cell death, thus confirming that mitochondrial Ca2+ uptake plays a key role in the process of apoptosis. These results reveal a novel function for the widely expressed VDAC channel, identifying it as a molecular component of the routes for Ca2+ transport across the mitochondrial membranes.

Key Words: organelle; calcium; apoptosis; signal transduction; porin


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