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Aspirin induces cell death by directly modulating mitochondrial voltage-dependent anion channel (VDAC).

ABSTRACT: Aspirin induces apoptotic cell death in various cancer cell lines. Here we showed that silencing of VDAC1 protected HeLa cells from aspirin-induced cell death. Compared to the wild type cells, VDAC1 knocked down cells showed lesser change of mitochondrial membrane potential (??m), upon aspirin treatment. Aspirin augmented ATP and ionomycin-induced mitochondrial Ca2+ uptake which was abolished in VDAC1 knocked down cells. Aspirin dissociated bound hexokinase II (HK-II) from mitochondria. Further, aspirin promoted the closure of recombinant human VDAC1, reconstituted in planar lipid bilayer. Taken together, these results imply that VDAC1 serves as a novel target for aspirin. Modulation of VDAC1 is possibly associated with the cell death and anticancer effects of aspirin.

SUBMITTER: Tewari D

PROVIDER: S-EPMC5361111 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Aspirin induces cell death by directly modulating mitochondrial voltage-dependent anion channel (VDAC).

Tewari Debanjan D Majumdar Dhriti D Vallabhaneni Sirisha S Bera Amal Kanti AK

Scientific reports 20170322

Aspirin induces apoptotic cell death in various cancer cell lines. Here we showed that silencing of VDAC1 protected HeLa cells from aspirin-induced cell death. Compared to the wild type cells, VDAC1 knocked down cells showed lesser change of mitochondrial membrane potential (Δψ<sub>m</sub>), upon aspirin treatment. Aspirin augmented ATP and ionomycin-induced mitochondrial Ca<sup>2+</sup> uptake which was abolished in VDAC1 knocked down cells. Aspirin dissociated bound hexokinase II (HK-II) from ...[more]

PMID: 28327594

Similar Datasets

Involvement of voltage-dependent anion channel (VDAC) in dengue infection.

Project description:During infection, dengue virus (DENV) proteins interact with host cellular constituents promoting the remodeling of the cell to facilitate virus production. While a number of interacting proteins have been identified for DENV non-structural proteins, far fewer interacting partners have been identified for the DENV structural proteins. One protein that has been identified as a DENV E protein interacting protein is the cellular chaperone GRP78. GRP78 has been shown to have a number of cellular interacting partners including the voltage-dependent anion channel (VDAC). In this study we confirmed the interactions between GRP78 and DENV E protein and between GRP78 and VDAC. VDAC was shown to be re-localized during DENV infection, with no change in levels of protein expression. VDAC is predominantly located on the outer membrane of mitochondria and our result is consistent with movement of the mitochondria towards the ER during DENV infection. Down regulation of VDAC through siRNA significantly reduced DENV protein expression, as well as the percentage infection and output virus titer. Our results suggest that VDAC plays an important role in DENV infection.

| S-EPMC5078847 | biostudies-other

Loss of voltage dependent anion channel 1 affects mitochondrial bioenergetics in rat dopamine cells

Project description:Voltage dependent anion channel 1 (VDAC1) is a multi-functional protein that regulates mitochondrial membrane potential, calcium regulation, and apoptosis. VDAC1 also interacts with a number of signaling pathways important for energy homeostasis and proteins involved in neurodegenerative diseases such as alpha-synuclein. To identify novel signaling pathways dependent upon VDAC1 protein in dopamine cells, we used CRISPR-Cas9 gene editing in rat immortalized dopaminergic N27 cells. Western blot confirmed that VDAC1 protein levels were reduced ~90%. Mitochondrial bioenergetics was assessed to determine if there was functional loss of mitochondrial function without VDAC1. Loss of VDAC1 resulted in lower ATP-linked and maximum respiration, and spare respiratory capacity. Transcriptomics was conducted in these cells to identify the pathways perturbed by loss of VDAC. This study sheds novel insight into the different regulatory roles mediated by VDAC1 in dopamine cells.

2019-07-31 | GSE118737 | GEO

Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration.

Project description:Regulation of mitochondrial outer membrane (MOM) permeability has dual importance: in normal metabolite and energy exchange between mitochondria and cytoplasm and thus in control of respiration, and in apoptosis by release of apoptogenic factors into the cytosol. However, the mechanism of this regulation, dependent on the voltage-dependent anion channel (VDAC), the major channel of MOM, remains controversial. A long-standing puzzle is that in permeabilized cells, adenine nucleotide translocase (ANT) is less accessible to cytosolic ADP than in isolated mitochondria. We solve this puzzle by finding a missing player in the regulation of MOM permeability: the cytoskeletal protein tubulin. We show that nanomolar concentrations of dimeric tubulin induce voltage-sensitive reversible closure of VDAC reconstituted into planar phospholipid membranes. Tubulin strikingly increases VDAC voltage sensitivity and at physiological salt conditions could induce VDAC closure at <10 mV transmembrane potentials. Experiments with isolated mitochondria confirm these findings. Tubulin added to isolated mitochondria decreases ADP availability to ANT, partially restoring the low MOM permeability (high apparent K(m) for ADP) found in permeabilized cells. Our findings suggest a previously unknown mechanism of regulation of mitochondrial energetics, governed by VDAC and tubulin at the mitochondria-cytosol interface. This tubulin-VDAC interaction requires tubulin anionic C-terminal tail (CTT) peptides. The significance of this interaction may be reflected in the evolutionary conservation of length and anionic charge in CTT throughout eukaryotes, despite wide changes in the exact sequence. Additionally, tubulins that have lost significant length or anionic character are only found in cells that do not have mitochondria.

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MicroED structure of lipid-embedded mammalian mitochondrial voltage-dependent anion channel.

Project description:A structure of the murine voltage-dependent anion channel (VDAC) was determined by microcrystal electron diffraction (MicroED). Microcrystals of an essential mutant of VDAC grew in a viscous bicelle suspension, making it unsuitable for conventional X-ray crystallography. Thin, plate-like crystals were identified using scanning-electron microscopy (SEM). Crystals were milled into thin lamellae using a focused-ion beam (FIB). MicroED data were collected from three crystal lamellae and merged for completeness. The refined structure revealed unmodeled densities between protein monomers, indicative of lipids that likely mediate contacts between the proteins in the crystal. This body of work demonstrates the effectiveness of milling membrane protein microcrystals grown in viscous media using a focused ion beam for subsequent structure determination by MicroED. This approach is well suited for samples that are intractable by X-ray crystallography. To our knowledge, the presented structure is a previously undescribed mutant of the membrane protein VDAC, crystallized in a lipid bicelle matrix and solved by MicroED.

| S-EPMC7768720 | biostudies-literature

Ten Years of High Resolution Structural Research on the Voltage Dependent Anion Channel (VDAC)-Recent Developments and Future Directions.

Project description:Mitochondria are evolutionarily related to Gram-negative bacteria and both comprise two membrane systems with strongly differing protein composition. The major protein in the outer membrane of mitochondria is the voltage-dependent anion channel (VDAC), which mediates signal transmission across the outer membrane but also the exchange of metabolites, most importantly ADP and ATP. More than 30 years after its discovery three identical high-resolution structures were determined in 2008. These structures show a 19-stranded anti-parallel beta-barrel with an N-terminal helix located inside. An odd number of beta-strands is also shared by Tom40, another member of the VDAC superfamily. This indicates that this superfamily is evolutionarily relatively young and that it has emerged in the context of mitochondrial evolution. New structural information obtained during the last decade on Tom40 can be used to cross-validate the structure of VDAC and vice versa. Interpretation of biochemical and biophysical studies on both protein channels now rests on a solid basis of structural data. Over the past 10 years, complementary structural and functional information on proteins of the VDAC superfamily has been collected from in-organello, in-vitro, and in silico studies. Most of these findings have confirmed the validity of the original structures. This short article briefly reviews the most important advances on the structure and function of VDAC superfamily members collected during the last decade and summarizes how they enhanced our understanding of the channel.

| S-EPMC5845903 | biostudies-literature

The Mitochondrial Voltage-Dependent Anion Channel 1, Ca2+ Transport, Apoptosis, and Their Regulation.

Project description:In the outer mitochondrial membrane, the voltage-dependent anion channel 1 (VDAC1) functions in cellular Ca2+ homeostasis by mediating the transport of Ca2+ in and out of mitochondria. VDAC1 is highly Ca2+-permeable and modulates Ca2+ access to the mitochondrial intermembrane space. Intramitochondrial Ca2+ controls energy metabolism by enhancing the rate of NADH production via modulating critical enzymes in the tricarboxylic acid cycle and fatty acid oxidation. Mitochondrial [Ca2+] is regarded as an important determinant of cell sensitivity to apoptotic stimuli and was proposed to act as a "priming signal," sensitizing the organelle and promoting the release of pro-apoptotic proteins. However, the precise mechanism by which intracellular Ca2+ ([Ca2+]i) mediates apoptosis is not known. Here, we review the roles of VDAC1 in mitochondrial Ca2+ homeostasis and in apoptosis. Accumulated evidence shows that apoptosis-inducing agents act by increasing [Ca2+]i and that this, in turn, augments VDAC1 expression levels. Thus, a new concept of how increased [Ca2+]i activates apoptosis is postulated. Specifically, increased [Ca2+]i enhances VDAC1 expression levels, followed by VDAC1 oligomerization, cytochrome c release, and subsequently apoptosis. Evidence supporting this new model suggesting that upregulation of VDAC1 expression constitutes a major mechanism by which apoptotic stimuli induce apoptosis with VDAC1 oligomerization being a molecular focal point in apoptosis regulation is presented. A new proposed mechanism of pro-apoptotic drug action, namely Ca2+-dependent enhancement of VDAC1 expression, provides a platform for developing a new class of anticancer drugs modulating VDAC1 levels via the promoter and for overcoming the resistance of cancer cells to chemotherapy.

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The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease.

Project description:The voltage-dependent anion channel (VDAC) is a β-barrel membrane protein located in the outer mitochondrial membrane (OMM). VDAC has two conductance states: an open anion selective state, and a closed and slightly cation-selective state. VDAC conductance states play major roles in regulating permeability of ATP/ADP, regulation of calcium homeostasis, calcium flux within ER-mitochondria contact sites, and apoptotic signaling events. Three reported structures of VDAC provide information on the VDAC open state via X-ray crystallography and nuclear magnetic resonance (NMR). Together, these structures provide insight on how VDAC aids metabolite transport. The interaction partners of VDAC, together with the permeability of the pore, affect the molecular pathology of diseases including Parkinson's disease (PD), Friedreich's ataxia (FA), lupus, and cancer. To fully address the molecular role of VDAC in disease pathology, major questions must be answered on the structural conformers of VDAC. For example, further information is needed on the structure of the closed state, how binding partners or membrane potential could lead to the open/closed states, the function and mobility of the N-terminal α-helical domain of VDAC, and the physiological role of VDAC oligomers. This review covers our current understanding of the various states of VDAC, VDAC interaction partners, and the roles they play in mitochondrial regulation pertaining to human diseases.

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A role for voltage-dependent anion channel Vdac1 in polyglutamine-mediated neuronal cell death.

Project description:Expansion of trinucleotide repeats in coding and non-coding regions of genes is associated with sixteen neurodegenerative disorders. However, the molecular effects that lead to neurodegeneration have remained elusive. We have explored the role of transcriptional dysregulation by TATA-box binding protein (TBP) containing an expanded polyglutamine stretch in a mouse neuronal cell culture based model. We find that mouse neuronal cells expressing a variant of human TBP harboring an abnormally expanded polyQ tract not only form intranuclear aggregates, but also show transcription dysregulation of the voltage dependent anion channel, Vdac1, increased cytochrome c release from the mitochondria and upregulation of genes involved in localized neuronal translation. On the other hand, unfolded protein response seemed to be unaffected. Consistent with an increased transcriptional effect, we observe an elevated promoter occupancy by TBP in vivo in TATA containing and TATA-less promoters of differentially expressed genes. Our study suggests a link between transcriptional dysfunction and cell death in trinucleotide repeat mediated neuronal dysfunction through voltage dependent anion channel, Vdac1, which has been recently recognized as a critical determinant of cell death.

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A chemical glycoproteomics platform reveals O-GlcNAcylation of mitochondrial voltage-dependent anion channel 2.

Project description:Protein modification by O-linked ?-N-acetylglucosamine (O-GlcNAc) is a critical cell signaling modality, but identifying signal-specific O-GlcNAcylation events remains a significant experimental challenge. Here, we describe a method for visualizing and analyzing organelle- and stimulus-specific O-GlcNAcylated proteins and use it to identify the mitochondrial voltage-dependent anion channel 2 (VDAC2) as an O-GlcNAc substrate. VDAC2(-/-) cells resist the mitochondrial dysfunction and apoptosis caused by global O-GlcNAc perturbation, demonstrating a functional connection between O-GlcNAc signaling and mitochondrial physiology through VDAC2. More broadly, our method will enable the discovery of signal-specific O-GlcNAcylation events in a wide array of experimental contexts.

| S-EPMC3869705 | biostudies-literature

Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity.

Project description:Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca(2+) handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca(2+) extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca(2+) uptake and accelerates the transfer of Ca(2+) from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca(2+) sparks and thereby inhibits Ca(2+) overload-induced erratic Ca(2+) waves and irregular contractions. We further show that overexpression of VDAC2 recapitulates the suppressive effect of efsevin on tremblor embryos whereas VDAC2 deficiency attenuates efsevin's rescue effect and that VDAC2 functions synergistically with MCU to suppress cardiac fibrillation in tremblor. Together, these findings demonstrate a critical modulatory role for VDAC2-dependent mitochondrial Ca(2+) uptake in the regulation of cardiac rhythmicity.

| S-EPMC4293673 | biostudies-literature

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