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

Rostovtseva, Tatiana K.; Kazemi, Namdar; Weinrich, Michael; Bezrukov, Sergey M.

doi:10.1074/jbc.m602548200

Cited by 118 publications

(201 citation statements)

References 93 publications

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“…VDAC forms a large voltagegated pore at the planar bilayer of mitochondria and acts as the major channel, allowing the flux of both anions and cations, with selectivity varying with the voltage-dependent "open" or "closed" state of the VDAC channel (16). An intact mitochondrial bilayer is essential for VDAC structure and function (17). We therefore investigated the GA-VDAC binding with purified mitochondria using buffers free of detergent.…”

mentioning

confidence: 99%

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

Xie

Wondergem

Shen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Geldanamycin and its derivative 17AAG [17-(Allylamino)-17-demethoxygeldanamycin, telatinib] bind selectively to the Hsp90 chaperone protein and inhibit its function. We discovered that these drugs associate with mitochondria, specifically to the mitochondrial membrane voltage-dependent anion channel (VDAC) via a hydrophobic interaction that is independent of HSP90. In vitro, 17AAG functions as a Ca 2+ mitochondrial regulator similar to benzoquinone-ubiquinones like Ub0. All of these compounds increase intracellular Ca 2+ and diminish the plasma membrane cationic current, inhibiting urokinase activity and cell invasion. In contrast, the HSP90 inhibitor radicicol, lacking a bezoquinone moiety, has no measurable effect on cationic current and is less effective in influencing intercellular Ca 2+ concentration. We conclude that some of the effects of 17-AAG and other ansamycins are due to their effects on VDAC and that this may play a role in their clinical activity.

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mentioning

confidence: 99%

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

Xie

Wondergem

Shen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…VDAC Reconstitution and Conductance MeasurementsPlanar lipid membranes were formed on a 70 -90 m diameter orifice in a 15-m-thick Teflon partition that separated two chambers as described previously (25). Lipid monolayers used for membrane formation were made from a 5 mg/ml solution of diphytanoylphosphatidylcholine (Avanti Polar Lipids, Inc.) in pentane.…”

Section: Methodsmentioning

confidence: 99%

“…10 and as described in Ref. 25. Two gating parameters (n, which is the effective gating charge and is the measure of the voltage-dependence steepness, and V 0 , the voltage at which half of the channels are open and half are closed) were calculated from the open probability plots following Ref.…”

Section: Methodsmentioning

confidence: 99%

“…Two gating parameters (n, which is the effective gating charge and is the measure of the voltage-dependence steepness, and V 0 , the voltage at which half of the channels are open and half are closed) were calculated from the open probability plots following Ref. 10 as described previously (25). Plot fitting was performed through the logarithmic version of the Boltzman distribution equation (25).…”

Section: Methodsmentioning

confidence: 99%

“…10 as described previously (25). Plot fitting was performed through the logarithmic version of the Boltzman distribution equation (25).…”

Section: Methodsmentioning

confidence: 99%

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Affixing N-terminal α-Helix to the Wall of the Voltage-dependent Anion Channel Does Not Prevent Its Voltage Gating

Teijido

Ujwal

Hillerdal

et al. 2012

Journal of Biological Chemistry

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Background: There is ongoing controversy concerning the location and mobility of the N-terminal ␣-helix in VDAC1 during voltage gating. Results: mVDAC1 with the N-terminal ␣-helix cross-linked to ␤-strand 11 forms typical voltage-gated channels. Conclusion:The N-terminal domain of VDAC1 does not move independently during voltage gating. Significance: This study dramatically alters the current view of voltage gating dynamic in VDAC1.The voltage-dependent anion channel (VDAC) governs the free exchange of ions and metabolites between the mitochondria and the rest of the cell. The three-dimensional structure of VDAC1 reveals a channel formed by 19 ␤-strands and an N-terminal ␣-helix located near the midpoint of the pore. The position of this ␣-helix causes a narrowing of the cavity, but ample space for metabolite passage remains. The participation of the N-terminus of VDAC1 in the voltage-gating process has been well established, but the molecular mechanism continues to be debated; however, the majority of models entail large conformational changes of this N-terminal segment. Here we report that the pore-lining N-terminal ␣-helix does not undergo independent structural rearrangements during channel gating. We engineered a double Cys mutant in murine VDAC1 that cross-links the ␣-helix to the wall of the ␤-barrel pore and reconstituted the modified protein into planar lipid bilayers. The modified murine VDAC1 exhibited typical voltage gating. These results suggest that the N-terminal ␣-helix is located inside the pore of VDAC in the open state and remains associated with ␤-strand 11 of the pore wall during voltage gating.The voltage-dependent anion channel (VDAC) 4 serves as the primary conduit between the mitochondria and the rest of the cell, facilitating free exchange of ions and metabolites across the outer mitochondrial membrane. In addition to its metabolic and energetic functions, VDAC has a more complex role, serving as a receptor for molecules and proteins that modulate the organelle's permeability and thereby its function (1-3). This multifunctional channel has been implicated in the metabolic stresses of cancer, cardiovascular disease, and mitochondrialdependent cell death (4 -8); thus, understanding the structure and function of VDAC constitutes a critical objective for basic as well as medical research.Single channel conductance experiments on VDAC1 at low membrane potential (Ͻ30 mV) reveal a high conductance (4.1 Ϯ 0.1 nanosiemens in 1 M KCl) indicative of a large pore, usually referred to as the "open" state of the channel (1). This conformer facilitates the passage of 10 6 ATP molecules (9) and displays a preference for monovalent anions over cations with the anion-to-cation permeability ratio of 2:1 in high salt (10) and 4:1 in physiological salt concentration (11). As voltage is increased (Ͼ30 mV) in either a positive or a negative direction, the channel switches into the lower conducting states (around 2 nanosiemens in 1 M KCl), termed as the "closed" state(s). These states are cation-selective wi...

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Plasmalogen‐rich foods promote the formation of cubic membranes in amoeba Chaos under stress conditions

et al. 2021

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Previous studies have indicated that the ability to form cubic membrane (CM), a three‐dimensional periodic structure with cubic symmetry, in amoeba (Chaos carolinense) under stress conditions depends on the type of food organism supplied before cell starvation. The significant increase in docosapentaenoic acid (DPA; C22:5n‐6) during the starvation period has been reported to induce CM formation and support Chaos cell survival. In this article, we further investigated the lipid profiles of food organisms of the Chaos cells to reveal the key lipid components that might promote CM formation. Our results show that the lipids extracted from cells of the native food organism Paramecium multimicronucleatum are enriched in plasmalogens. More specifically, plasmalogen phosphatidylcholine and plasmalogen phosphatidylethanolamine might be the key lipids that trigger CM formation in Chaos cells under starvation stress conditions. Unexpectedly, CM formation in these cells is not supported when the native food organism was replaced with plasmalogen‐deficit Tetrahymena pyriformis cells. Based on a previous lipidomics study on amoeba Chaos and this study on the lipid composition of its food organisms, three key lipids (plasmalogen phosphatidylcholine, plasmalogen phosphatidylethanolamine and diacyl‐phosphatidylinositol) were identified and used for liposomal construction. Our in vitro study revealed the potential role of these lipids in a nonlamellar phase transition. The negative staining transmission electron microscopy data of our liposomal constructs support the notion that plasmalogens may curve the membrane, which, in turn, may facilitate membrane fusion and vesicular formation, which is crucial for membrane dynamics and trafficking.

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

Cited by 118 publications

References 93 publications

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

Affixing N-terminal α-Helix to the Wall of the Voltage-dependent Anion Channel Does Not Prevent Its Voltage Gating

Plasmalogen‐rich foods promote the formation of cubic membranes in amoeba Chaos under stress conditions

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