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J. Biol. Chem., Vol. 281, Issue 25, 17347-17358, June 23, 2006

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Ca²⁺-dependent Control of the Permeability Properties of the Mitochondrial Outer Membrane and Voltage-dependent Anion-selective Channel (VDAC)^*

From the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Cell function depends on the distribution of cytosolic and mitochondrial factors across the outer mitochondrial membrane (OMM). Passage of metabolites through the OMM has been attributed to the voltage-dependent anion-selective channel (VDAC), which can form a large conductance and permanently open a channel in lipid bilayers. However, recent data indicate that the transport of metabolites through the OMM is controlled in the cells. Recognizing that the bilayer studies had been commonly conducted at supraphysiological [Ca²⁺] and [K⁺], we determined the effect of Ca²⁺ on VDAC activity. In liposomes, the purified VDAC displays Ca²⁺-dependent control of the molecular cut-off size and shows Ca²⁺-regulated Ca²⁺ permeability in the physiological [Ca²⁺] range. In bilayer experiments, at submicromolar [Ca²⁺], the purified VDAC or isolated OMM does not show sustained large conductance but rather exhibits gating between a nonconducting state and various subconductance states. Ca²⁺ addition causes a reversible increase in the conductance and may evoke channel opening to full conductance. Furthermore, single cell imaging data indicate that Ca²⁺ may facilitate the cation and ATP transport across the OMM. Thus, the VDAC gating is dependent on the physiological concentrations of cations, allowing the OMM to control the passage of ions and some small molecules. The OMM barrier is likely to decrease during the calcium signal.

Received for publication, January 30, 2006 , and in revised form, April 5, 2006.

^* This work was supported by National Institutes of Health Grant DK51526 (to G. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology, Anatomy and Cell Biology, Suite 261 JAH, Thomas Jefferson University, Philadelphia, PA 19107. Tel.: 215-503-1427; Fax: 215-923-2218; E-mail: gyorgy.hajnoczky{at}jefferson.edu.

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