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J. Biol. Chem., Vol. 281, Issue 49, 37496-37506, December 8, 2006

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Voltage Gating of VDAC Is Regulated by Nonlamellar Lipids of Mitochondrial Membranes^*

Tatiana K. Rostovtseva¹, Namdar Kazemi, Michael Weinrich, and Sergey M. Bezrukov

From the Laboratory of Physical and Structural Biology and National Center for Medical Rehabilitation Research, NICHD, National Institutes of Health, Bethesda, Maryland 20892

Evidence is accumulating that lipids play important roles in permeabilization of the mitochondria outer membrane (MOM) at the early stage of apoptosis. Lamellar phosphatidylcholine (PC) and nonlamellar phosphatidylethanolamine (PE) lipids are the major membrane components of the MOM. Cardiolipin (CL), the characteristic lipid from the mitochondrial inner membrane, is another nonlamellar lipid recently shown to play a role in MOM permeabilization. We investigate the effect of these three key lipids on the gating properties of the voltage-dependent anion channel (VDAC), the major channel in MOM. We find that PE induces voltage asymmetry in VDAC current-voltage characteristics by promoting channel closure at cis negative applied potentials. Significant asymmetry is also induced by CL. The observed differences in VDAC behavior in PC and PE membranes cannot be explained by differences in the insertion orientation of VDAC in these membranes. Rather, it is clear that the two nonlamellar lipids affect VDAC gating. Using gramicidin A channels as a tool to probe bilayer mechanics, we show that VDAC channels are much more sensitive to the presence of CL than could be expected from the experiments with gramicidin channels. We suggest that this is due to the preferential insertion of VDAC into CL-rich domains. We propose that the specific lipid composition of the mitochondria outer membrane and/or of contact sites might influence MOM permeability by regulating VDAC gating.

Received for publication, March 17, 2006 , and in revised form, September 20, 2006.

^* This research was supported by the Intramural Research Program of NICHD, National Institutes of Health. 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: Laboratory of Physical and Structural Biology, NICHD, National Institutes of Health, Bldg. 9, Rm. 1E-106, Bethesda, MD 20892. Tel.: 301-402-4702; Fax: 301-496-2172; E-mail: rostovtt{at}mail.nih.gov.

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