Is there VDAC in cell compartments other than the mitochondria?

Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland 97201, USA.
Journal of Bioenergetics (Impact Factor: 3.21). 05/1996; 28(2):93-100. DOI: 10.1007/BF02110638
Source: PubMed


Higher eukaryotes, including mammals and plants, express a family of VDAC proteins each encoded by a distinct gene. Two human genes encoding VDAC isoforms (HVDAC1 and HVDAC2) have been characterized in greatest detail. These genes generate three proteins that differ primarily by the addition of distinct N terminal extensions in HVDAC2 and HVDAC2', a splice variant of HVDAC2, relative to HVDAC1. Since N terminal sequences have been demonstrated to target many proteins to appropriate subcellular compartments, this observation raises the possibility that the N terminal differences found in HVDAC isoforms may lead to targeting of each protein to different cellular locations. Consistent with this hypothesis, a large number of reports have provided evidence consistent with the notion that HVDAC1 and its homolog in related mammalian species may specifically be present in the plasma membrane or other nonmitochondrial cellular compartments. Here, we review this information and conclude that if VDAC molecules are present at nonmitochondrial locations in mammalian cells, these are unlikely to be the known products of the HVDAC1 or HVDAC2 genes.

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    • "VDAC1 was once thought to be localized solely to the OMM (Yu and Forte, 1996). Indeed, although VDAC is present in abundance in the OMM, various studies have revealed that VDAC is also localized to cell compartments other than mitochondria (Bathori et al., 2000; Shoshan-Barmatz and Israelson, 2005; De Pinto et al., 2010b). "
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    ABSTRACT: Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to cancer. Found at the outer mitochondrial membrane, VDAC1 assumes a crucial position in the cell, controlling the metabolic cross-talk between mitochondria and the rest of the cell. Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC1 to interact with proteins that mediate and regulate the integration of mitochondrial functions with other cellular activities. As a metabolite transporter, VDAC1 contributes to the metabolic phenotype of cancer cells. This is reflected by VDAC1 over-expression in many cancer types, and by inhibition of tumor development upon silencing VDAC1 expression. Along with regulating cellular energy production and metabolism, VDAC1 is also a key protein in mitochondria-mediated apoptosis, participating in the release of apoptotic proteins and interacting with anti-apoptotic proteins. The involvement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space is discussed, as is VDAC1 oligomerization as an important step in apoptosis induction. VDAC also serves as an anchor point for mitochondria-interacting proteins, some of which are also highly expressed in many cancers, such as hexokinase (HK), Bcl2, and Bcl-xL. By binding to VDAC, HK provides both metabolic benefit and apoptosis-suppressive capacity that offers the cell a proliferative advantage and increases its resistance to chemotherapy. VDAC1-based peptides that bind specifically to HK, Bcl2, or Bcl-xL abolished the cell's abilities to bypass the apoptotic pathway. Moreover, these peptides promote cell death in a panel of genetically characterized cell lines derived from different human cancers. These and other functions point to VDAC1 as a rational target for the development of a new generation of therapeutics.
    Frontiers in Oncology 11/2012; 2:164. DOI:10.3389/fonc.2012.00164
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    • "It should be noted, that not all the studies were consistent with the plasmalemmal expression of VDAC. Thus, in the reports by Yu and co-authors [41] [42], the human VDAC1 and VDAC2 proteins were tagged with FLAG epitope or human influenza hemagglutininderived epitope; the constructs then were expressed in COS7 cells or in cultured astrocytes, and subcellular localization was analyzed by membrane fractionation, immunocytochemistry, and immunogold electron microscopy. The heterologously expressed recombinant VDAC proteins could be detected exclusively in the mitochondria. "
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    ABSTRACT: The maxi-anion channel has been observed in many cell types from the very beginning of the patch-clamp era. The channel is highly conductive for chloride and thus can modulate the resting membrane potential and play a role in fluid secretion/absorption and cell volume regulation. A wide nanoscopic pore of the maxi-anion channel permits passage of excitatory amino acids and nucleotides. The channel-mediated release of these signaling molecules is associated with kidney tubuloglomerular feedback, cardiac ischemia/hypoxia, as well as brain ischemia/hypoxia and excitotoxic neurodegeneration. Despite the ubiquitous expression and physiological/pathophysiological significance, the molecular identity of the maxi-anion channel is still obscure. VDAC is primarily a mitochondrial protein; however several groups detected it on the cellular surface. VDAC in lipid bilayers reproduced the most important biophysical properties of the maxi-anion channel, such as a wide nano-sized pore, closure in response to moderately high voltages, ATP-block and ATP-permeability. However, these similarities turned out to be superficial, and the hypothesis of plasmalemmal VDAC as the maxi-anion channel did not withstand the test by genetic manipulations of VDAC protein expression. VDAC on the cellular surface could also function as a ferricyanide reductase or a receptor for plasminogen kringle 5 and for neuroactive steroids. These ideas, as well as the very presence of VDAC on plasmalemma, remain to be scrutinized by genetic manipulations of the VDAC protein expression. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.
    Biochimica et Biophysica Acta 10/2011; 1818(6):1570-80. DOI:10.1016/j.bbamem.2011.09.024 · 4.66 Impact Factor
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    • "VDACs is a multigene family of evolutionarily conserved and well characterized porins found in outer mitochondrial membranes of all eukaryotes [25], where they control homeostasis by transport of ATP and ADP [26]. Numerous research groups also reported the presence of VDAC proteins in the plasma membrane of various cell types [27,28]. VDAC 1 contributed to ATP transport across the plasma membrane of murine cells [29], and could act as NADH-ferricyanide reductase to inhibit the release of synthesized ATP and greatly decrease the activity of exogenous NADH/cytochrome-c system of intact mitochondria [30], however the significance of its total absence from 3A10-3F on JEV infection is not reported. "
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    ABSTRACT: The pathogenesis of Japanese encephalitis virus (JEV) is not definitely elucidated as the initial interaction between virus and host cell receptors required for JEV infection is not clearly defined yet. Here, in order to discover those membrane proteins that may be involved in JEV attachment to or entry into virus permissive BHK-21 cells, a chemically mutated cell line (designated 3A10-3F) that became less susceptible to JEV infection was preliminarily established and selected by repeated low moi JEV challenges and RT-PCR detection for viral RNA E gene fragment. The susceptibility to JEV of 3A10-3F cells was significantly weakened compared with parental BHK-21 cells, verified by indirect immunofluorescence assay, virus plague formation assay, and flow cytometry. Finally, two-dimensional electrophoresis (2-DE) coupled with LC-MS/MS was utilized to recognize the most differentially expressed proteins from membrane protein extracts of 3A10-3F and BHK-21 cells respectively. The noted discrepancy of membrane proteins included calcium binding proteins (annexin A1, annexin A2), and voltage-dependent anion channels proteins (VDAC 1, VDAC 2), suggesting that these molecules may affect JEV attachment to and/or entry into BHK-21 cells and worthy of further investigation.
    Virology Journal 03/2011; 8:115. DOI:10.1186/1743-422X-8-115 · 2.18 Impact Factor
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