Disease relevance of VDAC1

• Changes of voltage-dependent anion-selective channel proteins VDAC1 and VDAC2 brain levels in patients with Alzheimer's disease and Down syndrome [1].
• Our data suggest that the Neisseria porin can, like its eukaryotic homologue, function at the mitochondrial checkpoint to mediate apoptosis [2].
• To unveil those interactions, we screened a human liver cDNA library with the phage display methodology optimized to target VDAC reconstituted into a membrane environment [3].
• Tissue-specific VDAC isoform 1 (HVDAC1) deficiency in human skeletal muscle is responsible of a rare mitochondrial encephalomyopathy, fatal in childhood [4].
• VDAC1 was detected in benign and malignant lesions, showing a strong positivity in follicular carcinomas [5].

High impact information on VDAC1

• A 223-amino acid protein in the outer mitochondrial membrane of most eukaryotic cells comprises a voltage-dependent anion channel [6].
• Both porin classes interact with purine nucleoside triphosphates, which down-regulate pore size and cause a shift in voltage dependence and ion selectivity [7].
• Only recombinant C4bp mutant molecules containing the NH2-terminal alpha-chain short consensus repeat (SCR1) bound to both Por1A and Por1B gonococci, suggesting that SCR1 contained Por binding sites [8].
• The neisserial porin P.I is a GTP binding protein that forms a voltage-gated channel that translocates into mammalian cell membranes and modulates host cell signaling events [9].
• Consistent with this, when nitrocellulose blots of whole L. pneumophila or bacterial components are incubated in fresh nonimmune serum, C3 fixes exclusively to the major outer membrane protein (MOMP) of L. pneumophila, a porin; C3 does not fix to L. pneumophila LPS on these blots [10].

Chemical compound and disease context of VDAC1

• This effect is oligomer length-dependent, and the ability of phosphorothioate homopolymers of thymidine of variable lengths to cause the release of cytochrome c from isolated mitochondria of 518A2 melanoma cells can be correlated with their ability to interact with VDAC [11].
• Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: possible role in apoptosis [12].
• Colocalization of BAX with BID and VDAC-1 in nimesulide-induced apoptosis of human colon adenocarcinoma COLO 205 cells [13].
• In anoxia, cytopathic hypoxia and ethanol treatment, reactive oxygen and nitrogen species, cytokines, kinase cascades and increased NADH act to inhibit VDAC conductance and promote selective oxidation of membrane-permeable respiratory substrates like short chain fatty acids and acetaldehyde [14].
• The Escherichia coli FepA protein is an energy- and TonB-dependent, ligand-binding porin that functions as a receptor for the siderophore ferric enterobactin and colicins B and D. We characterized the kinetic and thermodynamic parameters associated with the initial, energy-independent steps in ligand binding to FepA [15].

Biological context of VDAC1

• Our data suggest that a major function of VDAC1 in the plasma membrane is that of a NADH(-ferricyanide) reductase that may be involved in the maintenance of cellular redox homeostasis [16].
• The spots representing VDAC1 were separated with different p/s (p/7.5, 8.5, and 10.0) probably caused by post-translational modifications as, e.g., phosphorylation [1].
• Here, we report the mapping of VDAC1 to the X chromosome in the interval Xq13-q21 and VDAC2 to chromosome 21 by polymerase chain reaction and restriction analysis of a human/rodent somatic cell mapping panel [17].
• We propose a model on how electron transport may occur in VDAC1 [18].
• The promoter region of each VDAC isoform lacks a canonical TATA box, but all are G+C-rich, a characteristic of housekeeping gene promoters [19].

Anatomical context of VDAC1

• Glutamate 72 in VDAC1, shown previously to bind dicyclohexylcarbodiimide (DCCD), which inhibits hexokinase isoform I (HK-I) binding to mitochondria, was mutated to glutamine [20].
• Here we show that VDAC1, when expressed in the plasma membrane, functions as a NADH-ferricyanide reductase [16].
• Total VDAC1 was significantly decreased in frontal cortex and thalamus [1].
• Our results show that VDAC1 immunoreactivity corresponds to mitochondria and sarcoplasmic reticulum, while sarcolemmal reactivity, previously reported, was not observed [21].
• In contrast, VDAC1 (porin-1) is exclusively localized in Sertoli cells [22].

Associations of VDAC1 with chemical compounds

• However, this activity can be inhibited by thiol chelators, suggesting that at least one of the two cysteine groups present in VDAC1 are critical for electron transfer [18].
• Furthermore, NADH-dependent ferricyanide reduction associated with VDAC1 is not sensitive to the anion channel inhibitors DIDS and dextran sulfate [18].
• The biological meaning of our results may be derangement of voltage-dependent anion-selective channel function and reflecting impaired glucose, energy, and intermediary metabolism as well as apoptotic mechanisms [1].
• Dopamine indeed decreased the mitochondrial Delta(Psi)(m), but the maximum effect was observed within 3 h, prior to the decrease in VDAC mRNA or protein levels [23].
• Whether the decrease in VDAC expression influence the mitochondrial membrane potential (Delta(Psi)(m)) was determined with the dye Rhodamine-123 [23].

Physical interactions of VDAC1

• Hexokinase II binding to VDAC suppresses the release of intermembrane space proteins and inhibits apoptosis, thereby contributing to the survival advantage of tumor cells [24].
• Hexokinase and glycerol kinase interact with porin on the outer surface of the OMM in a manner which provides these enzymes with preferred access to the ATP generated in the mitochondrion [25].
• In the process of permeability transition induction, the death-inducing domain of HGTD-P physically interacted with the voltage-dependent anion channel [26].
• In vitro binding studies with glutathione S-transferase-porin indicated that porin binds directly to eNOS and that this interaction augmented eNOS activity [27].
• The structure of a peptide antigen corresponding to the subtype P1.7 variant of the porin PorA from the human pathogen Neisseria meningitidis was determined by solution of the X-ray crystal structure of the ternary complex of the peptide (ANGGASGQVK) in complex with a Fab fragment and a domain from streptococcal protein G to 1.95 A resolution [28].

Enzymatic interactions of VDAC1

• Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity [29].

Regulatory relationships of VDAC1

• In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death [30].
• Neisserial porin-induced dendritic cell activation is MyD88 and TLR2 dependent [31].
• Furthermore, voltage-dependent anion channel (VDAC) 1 was identified as a gene highly expressed in CD45(+) U266 by cDNA subtraction [32].
• BCS1L was strongly expressed in embryonic tissues already at embryonic days 7 (E7) and 9 whereas the expression of Porin and Rieske FeS was not as evident at this time point [33].
• Neisseria gonorrhoeae porin P1.B induces endosome exocytosis and a redistribution of Lamp1 to the plasma membrane [34].

Other interactions of VDAC1

• In DS cerebellum, total VDAC1 protein was elevated significantly whereas VDAC2 did not show any significant alterations [1].
• Indirect immunofluorescence on HeLa cells indicates a co-localisation of hVDAC1 with the dynein light chain and the PBP74 [35].
• The locations of VDAC1 and VDAC4 have been confirmed by fluorescence in situ hybridization analysis [17].
• In the present paper, a direct interaction of HK-I with bilayer-reconstituted purified VDAC, inducing channel closure, is demonstrated for the first time [30].
• Among the Bcl-2-unrelated, mitochondrion-targeted proteins, several interact with the voltage-dependent anion channel (VDAC) or with the adenine nucleotide translocator (ANT) [36].

Analytical, diagnostic and therapeutic context of VDAC1

• Their specificity was demonstrated by immunoblotting using recombinant VDAC1, -2, and -3 [37].
• Transfecting cells with pl-VDAC1-GFP, which carries an N-terminal signal peptide, directs VDAC1 to the plasma membrane, as shown by confocal microscopy and FACS analysis, and significantly increases the plasma membrane NADH-ferricyanide reductase activity of the transfected cells [16].
• Semi-quantitative PCR analysis indicated that expression of the three VDAC isoforms was reduced by dopamine [23].
• Infection of cell cultures with Neisseria gonorrhoeae results in apoptosis that is mediated by the PorB porin [2].
• Immunoprecipitation experiments revealed that PorB interacts with the mitochondrial porin VDAC (voltage-dependent anion channel) [38].

References