VDAC1 (voltage-dependent anion channel 1)

Review on VDAC1 (voltage-dependent anion channel 1), with data on DNA, on the protein encoded, and where the gene is implicated

The role of calcium in VDAC1 oligomerization and mitochondria-mediated apoptosis

AbstractThe voltage-dependent anion channel (VDAC), located at the outer mitochondria membrane (OMM), mediates interactions between mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca2+, and metabolites. Substantial evidence points to VDAC1 as being a key player in apoptosis, regulating the release of apoptogenic proteins from mitochondria, such as cytochrome c, and interacting with anti-apoptotic proteins. Recently, we demonstrated that VDAC1 oligomerization is a general mechanism common to numerous apoptogens acting via different initiating cascades and proposed that a protein-conducting channel formed within a VDAC1 homo/hetero oligomer mediates cytochrome c release. However, the molecular mechanism responsible for VDAC1 oligomerization remains unclear. Several studies have shown that mitochondrial Ca2+ is involved in apoptosis induction and that VDAC1 possesses Ca2+-binding sites and mediates Ca2+ transport across the OMM. Here, the relationship between the cellular Ca2+ level, [Ca2+]i, VDAC1 oligomerization and apoptosis was studied. Decreasing [Ca2+]i using the cell-permeable Ca2+ chelating reagent BAPTA-AM was found to inhibit VDAC1 oligomerization and apoptosis, while increasing [Ca2+]i using Ca2+ ionophore resulted in VDAC1 oligomerization and apoptosis induction in the absence of apoptotic stimuli. Moreover, induction of apoptosis elevated [Ca2+]i, concomitantly with VDAC1 oligomerization. AzRu-mediated inhibition of mitochondrial Ca2+ transport decreased VDAC1 oligomerization, suggesting that mitochondrial Ca2+ is required for VDAC1 oligomerization. In addition, increased [Ca2+]i levels up-regulate VDAC1 expression. These results suggest that Ca2+ promotes VDAC1 oligomerization via activation of a yet unknown signaling pathway or by increasing VDAC1 expression, leading to apoptosis. This article is part of a Special Issue entitled: 12th European Symposium on Calcium

Key regions of VDAC1 functioning in apoptosis induction and regulation by hexokinase

AbstractThe voltage-dependent anion channel (VDAC), located in the mitochondrial outer membrane, functions as gatekeeper for the entry and exit of mitochondrial metabolites, and thus controls cross-talk between mitochondria and the cytosol. VDAC also serves as a site for the docking of cytosolic proteins, such as hexokinase, and is recognized as a key protein in mitochondria-mediated apoptosis. The role of VDAC in apoptosis has emerged from various studies showing its involvement in cytochrome c release and apoptotic cell death as well as its interaction with proteins regulating apoptosis, including the mitochondria-bound isoforms of hexokinase (HK-I, HK-II). Recently, the functional HK–VDAC association has shifted from being considered in a predominantly metabolic light to the recognition of its major impact on the regulation of apoptotic responsiveness of the cell. Here, we demonstrate that the HK–VDAC1 interaction can be disrupted by mutating VDAC1 and by VDAC1-based peptides, consequently leading to diminished HK anti-apoptotic activity, suggesting that disruption of HK binding to VDAC1 can decrease tumor cell survival. Indeed, understanding structure–function relationships of VDAC is critical for deciphering how this channel can perform such a variety of differing functions, all important for cell life and death. By expressing VDAC1 mutants and VDAC1-based peptides, we have identified VDAC1 amino acid residues and domains important for interaction with HK and protection against apoptosis. These include negatively- and positively-charged residues, some of which are located within β-strands of the protein. The N-terminal region of VDAC1 binds HK-I and prevents HK-mediated protection against apoptosis induced by STS, while expression of a VDAC N-terminal peptide detaches HK-I-GFP from mitochondria. These findings indicate that the interaction of HK with VDAC1 involves charged residues in several β-strands and in the N-terminal domain. Displacing HK, serving as the ‘guardian of the mitochondrion’, from its binding site on VDAC1 may thus be exploited as an approach to cancer therapy

Altered expression of proteins in cancer: function and potential therapeutic targets

Copyright © 2022 Pessoa, Martins, Casimiro, Pérez-Plasencia and Shoshan-Barmatz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The design of innovative cancer treatments requires extensive characterization of the molecular and cellular alterations associated with tumor development and progression. Cancer cells show extensive alterations in protein expression levels, which are drivers of their malignant transformation. Proteins with altered expression levels in cancer are involved in protein synthesis and degradation, signaling and metabolic pathways, DNA repair, apoptosis, and other cellular processes, whose alterations cause tumor development and progression. Characterizing the mechanisms that lead to alterations in protein levels and their cellular effects is an invaluable tool for repurposing those proteins as drug targets. Examples of up-regulated proteins in cancer include the epidermal growth factor receptor 2 (HER2) and the vascular endothelial growth factor (VEGF). HER2 is up-regulated in several cancer types, including breast, gastroesophageal, and non-small-cell lung cancers, making it an effective drug target. VEGF is up-regulated in pancreatic, prostate, and colorectal cancers, among others. Its inhibition is also an effective anticancer treatment, through a decrease in tumor vascularization.These examples demonstrate the modulation of protein levels as an effective anticancer target, which is becoming widely used in patient treatments. These studies also encourage additional research to uncover and test novel up-/down-regulated proteins as potential new therapeutic targets.This work was financed by the European Regional Development Fund (ERDF), through the COMPETE 2020 – Operational Programme for Competitiveness and Internationalization and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia, under the projects POCI-01-0145-FEDER-028147 (VISCERAL), UIDB/04539/2020, UIDP/04539/2020, and LA/P/0058/2020 (to JP), and PTDC/MED-ONC/28636/2017 (to SC); by Programa de Financiamiento para la Investigación, UNAM, PAPIIT-IN231420, México (to CP-P); and by the National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University, Beer Sheva, Israel (to VS-B).info:eu-repo/semantics/publishedVersio

VDAC1 at the crossroads of cell metabolism, apoptosis and cell stress

This review presents current knowledge related to VDAC1 as a multi-functional mitochondrial protein acting on both sides of the coin, regulating cell life and death, and highlighting these functions in relation to disease. It is now recognized that VDAC1 plays a crucial role in regulating the metabolic and energetic functions of mitochondria. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows the control of metabolic cross-talk between mitochondria and the rest of the cell and also enables interaction of VDAC1 with proteins involved in metabolic and survival pathways. Along with regulating cellular energy production and metabolism, VDAC1 is also involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. VDAC1 functions in the release of apoptotic proteins located in the mitochondrial intermembrane space via oligomerization to form a large channel that allows passage of cytochrome c and AIF and their release to the cytosol, subsequently resulting in apoptotic cell death. VDAC1 also regulates apoptosis via interactions with apoptosis regulatory proteins, such as hexokinase, Bcl2 and Bcl-xL, some of which are also highly expressed in many cancers. This review also provides insight into VDAC1 function in Ca2+ homeostasis, oxidative stress, and presents VDAC1 as a hub protein interacting with over 100 proteins. Such interactions enable VDAC1 to mediate and regulate the integration of mitochondrial functions with cellular activities. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target

Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS

SummaryMutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons. With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. This interaction is found on isolated spinal cord mitochondria and can be reconstituted with purified components in vitro. ADP passage through the outer membrane is diminished in spinal mitochondria from mutant SOD1-expressing ALS rats. Direct binding of mutant SOD1 to VDAC1 inhibits conductance of individual channels when reconstituted in a lipid bilayer. Reduction of VDAC1 activity with targeted gene disruption is shown to diminish survival by accelerating onset of fatal paralysis in mice expressing the ALS-causing mutation SOD1G37R. Taken together, our results establish a direct link between misfolded mutant SOD1 and mitochondrial dysfunction in this form of inherited ALS