The Voltage-Dependent Anion Channel (VDAC): Function in Intracellular Signalling, Cell Life and Cell Death

Shoshan‐Barmatz, Varda; Israelson, Adrian; Brdiczka, Dieter; Sheu, Shey Shing

doi:10.2174/138161206777585111

Cited by 285 publications

(347 citation statements)

References 248 publications

(441 reference statements)

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“…In this study, the authors suggested that the effect of tBID on OMM permeabilization is through another unidentified OMM protein. The importance of VDAC for OMM permeabilization is further supported by recent evidence that overexpression of VDAC induces apoptosis in various cell types, and this effect is inhibited by BCL-2 and VDAC inhibitors [28,29].…”

Section: The Involvement Of Vdac In Apoptosismentioning

confidence: 75%

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

2007

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Mitochondria play a pivotal role in the process of apoptosis. Alterations in mitochondrial structure and function during apoptosis are regulated by proteins of the BCL-2 family, however their exact mechanism of action is largely unknown. Mitochondrial carriers and pores play an essential role in maintaining the normal function of mitochondria, and BCL-2 family members were shown to interact with several mitochondrial carriers/pores and to affect their function. This review focuses on the involvement of several of these mitochondrial carriers/pores in the regulation of the mitochondrial death pathway.

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Section: The Involvement Of Vdac In Apoptosismentioning

confidence: 75%

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

2007

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“…More recently it has become clear that the permeability of the OMM is actually regulated by the channels that transport these molecules, the VDACs (40). In 1979 it was predicted that these channels would be involved in regulating mitochondrial metabolism (41), and numerous studies in the ensuing decades have proven this prediction to be true (42)(43)(44)(45)(46). The name of the channel is somewhat misleading, because although it originally was thought to be anion selective, VDAC also has been shown to transport cations such as calcium and numerous small metabolites including ATP, ADP, NADH, pyruvate, and others (47,48).…”

Section: Discussionmentioning

confidence: 99%

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Head

Shi

Zhao

et al. 2015

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

111

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Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.

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“…The assignment of three residues in the N-terminal helix (K12, D16, and V17) benefited from the chemical shift information obtained from solidstate NMR (24). In total, five residues are assigned in the second half of the N-terminal helix (residues [12][13][14][15][16][17][18][19][20], demonstrating that this region is not broadened beyond detection by intermediate chemical exchange. This result is in line with the observation that peaks corresponding to residues A2-V17 give rise to distinct narrow crosspeaks in solid state NMR spectra of hVDAC1 reconstituted in liposomes, indicating a rather rigid conformation (24).…”

Section: μS-ms Dynamics Are Significantly Increased For the N-terminamentioning

confidence: 99%

“…Metabolite flow is regulated by a voltage-dependent conformational change between a high-conductance anionselective state, several low-conductance states favoring small cations (17,18), and a high-conductance cation-selective state (19). VDAC gating is furthermore modulated by a variety of ions, small molecules, apoptotic proteins of the Bcl-2 family, and hexokinase (20), strongly implicating VDAC's function in apoptosis regulation (21). To enable interactions and gating between various states, conformational variability of VDAC is expected.…”

mentioning

confidence: 99%

Functional dynamics in the voltage-dependent anion channel

Villinger

Briones

Giller

et al. 2010

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

105

129

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The voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, acts as a gatekeeper for the entry and exit of mitochondrial metabolites. Here we reveal functional dynamics of isoform one of VDAC (VDAC1) by a combination of solution NMR spectroscopy, Gaussian network model analysis, and molecular dynamics simulation. Micro-to millisecond dynamics are significantly increased for the N-terminal six β-strands of VDAC1 in micellar solution, in agreement with increased B-factors observed in the same region in the bicellar crystal structure of VDAC1. Molecular dynamics simulations reveal that a charge on the membrane-facing glutamic acid 73 (E73) accounts for the elevation of N-terminal protein dynamics as well as a thinning of the nearby membrane. Mutation or chemical modification of E73 strongly reduces the micro-to millisecond dynamics in solution. Because E73 is necessary for hexokinase-I-induced VDAC channel closure and inhibition of apoptosis, our results imply that microto millisecond dynamics in the N-terminal part of the barrel are essential for VDAC interaction and gating.membrane protein | molecular dynamics | NMR spectroscopy | protein-lipid interactions | structure D ynamics of proteins provide the essential link between structure and function. Membrane protein dynamics are gaining more attention due to an increasing number of high-resolution structures. A versatile experimental method for the study of membrane protein dynamics is NMR spectroscopy, providing atomic resolution information from nanoseconds to seconds (for an overview see ref. 1). In addition, when a three-dimensional structure is available, insight into fast dynamics of proteins, which occur on the nanosecond time scale, might be gained from molecular dynamics (MD) simulation and elastic network models (2, 3).NMR studies have revealed large conformational changes essential for the physiological function of α-helical membrane proteins, such as the interaction of phospholamban with effectors modulating heart muscle contractility (4, 5) and antimicrobial peptides adopting different conformations in membranes or solution (6, 7). Less well characterized are motions of outer membrane β-barrels. A pioneering solution NMR study revealed μs-ms interconversion of the catalytic loop of PagP between an excited and a nonexcited state, enabling both ligand binding and enzymatic catalysis (8). Nonenzymatic β-barrel channels exhibit more general dynamic features, such as loop flexibility and slow conformational exchange towards the extracellular barrel edges, altogether indicating relevance for substrate conductance and gating (9-11).The voltage-dependent anion channel (VDAC) is one of the few β-barrel membrane proteins, the structure of which has been determined to date (12-14). Serving as the major pass-through for metabolites between mitochondria and the cytosol (15), the highly abundant channel is regarded as a key regulator of cellular energy metabolism (16). Metabolite flow is regulated by a voltage-dependent conformational c...

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The Voltage-Dependent Anion Channel (VDAC): Function in Intracellular Signalling, Cell Life and Cell Death

Cited by 285 publications

References 248 publications

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Functional dynamics in the voltage-dependent anion channel

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