scholarly journals VDAC2 and the BCL-2 family of proteins

2021 ◽  
Author(s):  
Zheng Yuan ◽  
Grant Dewson ◽  
Peter E. Czabotar ◽  
Richard W. Birkinshaw
Keyword(s):  
Protein Interactions ◽  
Drug Targets ◽  
Current Knowledge ◽  
Anion Channel ◽  
Protein Family ◽  
Effector Proteins ◽  
Mitochondrial Apoptosis ◽  
Protein Protein Interactions ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent

The BCL-2 protein family govern whether a cell dies or survives by controlling mitochondrial apoptosis. As dysregulation of mitochondrial apoptosis is a common feature of cancer cells, targeting protein–protein interactions within the BCL-2 protein family is a key strategy to seize control of apoptosis and provide favourable outcomes for cancer patients. Non-BCL-2 family proteins are emerging as novel regulators of apoptosis and are potential drug targets. Voltage dependent anion channel 2 (VDAC2) can regulate apoptosis. However, it is unclear how this occurs at the molecular level, with conflicting evidence in the literature for its role in regulating the BCL-2 effector proteins, BAK and BAX. Notably, VDAC2 is required for efficient BAX-mediated apoptosis, but conversely inhibits BAK-mediated apoptosis. This review focuses on the role of VDAC2 in apoptosis, discussing the current knowledge of the interaction between VDAC2 and BCL-2 family proteins and the recent development of an apoptosis inhibitor that targets the VDAC2–BAK interaction.

scholarly journals Voltage-dependent anion channels 1 and 2 are expressed in porcine oocytes

2009 ◽  
Vol 30 (3) ◽  
pp. 193-200 ◽  
Author(s):  
María Carolina Cassará ◽  
Viviana Andrea Menzel ◽  
Klaus-Dieter Hinsch ◽  
Christine Wrenzycki ◽  
Elvira Hinsch
Keyword(s):  
Protein Interactions ◽  
Cortical Area ◽  
Intracellular Localization ◽  
Germinal Vesicle ◽  
Anion Channel ◽  
Confocal Laser ◽  
Protein Protein Interactions ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Porcine Oocyte

The eukaryotic VDAC (voltage-dependent anion channel) is a pore-forming protein originally discovered in the outer membrane of mitochondria. It has been established as a key player in mitochondrial metabolism and ion signalling. In addition, in recent years, it has also been proposed that VDAC is present in extra-mitochondrial membranes, and it has been related to cytoskeletal structures. However, little is known about the presence and intracellular localization of VDAC subtypes in mammalian gametes. In the present study, we confirm the synthesis of VDAC1 and 2 subtypes in GV (germinal vesicle) and MII (meiosis II) stage porcine oocytes as well as their protein expression. A shift in the abundance of immunoreactive 32 kDa VDAC protein between GV and MII stage oocytes was observed with anti-VDAC2 antibody. Furthermore, subcellular localization by confocal laser microscopy demonstrated fluorescent labelling of VDAC1 over the entire oocyte surface, suggesting the presence of VDAC1 in the porcine oocyte plasma membrane and around the cortical area. Anti-VDAC2 immunostaining yielded ring-like clusters of structures distributed on the cortical area in some GV, but not in MII, stage oocytes. These results are the first data obtained for VDAC in mammalian female gametes and provide the basis for studying protein–protein interactions, distribution and possible functions of VDAC subtypes during maturation and fertilization of mammalian oocytes.

scholarly journals Structure, gating and interactions of the voltage-dependent anion channel

2021 ◽  
Vol 50 (2) ◽  
pp. 159-172 ◽  
Author(s):  
Eszter E. Najbauer ◽  
Stefan Becker ◽  
Karin Giller ◽  
Markus Zweckstetter ◽  
Adam Lange ◽  
...  
Keyword(s):  
Drug Targets ◽  
Anion Channel ◽  
Magic Angle Spinning ◽  
Voltage Gating ◽  
Magic Angle ◽  
Outer Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Angle Spinning ◽  
Potential Drug Targets

AbstractThe voltage-dependent anion channel (VDAC) is one of the most highly abundant proteins found in the outer mitochondrial membrane, and was one of the earliest discovered. Here we review progress in understanding VDAC function with a focus on its structure, discussing various models proposed for voltage gating as well as potential drug targets to modulate the channel’s function. In addition, we explore the sensitivity of VDAC structure to variations in the membrane environment, comparing DMPC-only, DMPC with cholesterol, and near-native lipid compositions, and use magic-angle spinning NMR spectroscopy to locate cholesterol on the outside of the β-barrel. We find that the VDAC protein structure remains unchanged in different membrane compositions, including conditions with cholesterol.

scholarly journals VDAC1 in the diseased myocardium and the effect of VDAC1-interacting compound on atrial fibrosis induced by hyperaldosteronism

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hadar Klapper-Goldstein ◽  
Ankit Verma ◽  
Sigal Elyagon ◽  
Roni Gillis ◽  
Michael Murninkas ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Apoptotic Cell ◽  
Anion Channel ◽  
Immunohistochemical Analysis ◽  
Voltage Dependent Anion Channel ◽  
Cardiac Tissues ◽  
Therapeutic Implications ◽  
Voltage Dependent ◽  
Models Of Lupus

AbstractThe voltage-dependent anion channel 1 (VDAC1) is a key player in mitochondrial function. VDAC1 serves as a gatekeeper mediating the fluxes of ions, nucleotides, and other metabolites across the outer mitochondrial membrane, as well as the release of apoptogenic proteins initiating apoptotic cell death. VBIT-4, a VDAC1 oligomerization inhibitor, was recently shown to prevent mitochondrial dysfunction and apoptosis, as validated in mouse models of lupus and type-2 diabetes. In the present study, we explored the expression of VDAC1 in the diseased myocardium of humans and rats. In addition, we evaluated the effect of VBIT-4 treatment on the atrial structural and electrical remodeling of rats exposed to excessive aldosterone levels. Immunohistochemical analysis of commercially available human cardiac tissues revealed marked overexpression of VDAC1 in post-myocardial infarction patients, as well as in patients with chronic ventricular dilatation\dysfunction. In agreement, rats exposed to myocardial infarction or to excessive aldosterone had a marked increase of VDAC1 in both ventricular and atrial tissues. Immunofluorescence staining indicated a punctuated appearance typical for mitochondrial-localized VDAC1. Finally, VBIT-4 treatment attenuated the atrial fibrotic load of rats exposed to excessive aldosterone without a notable effect on the susceptibility to atrial fibrillation episodes induced by burst pacing. Our results indicate that VDAC1 overexpression is associated with myocardial abnormalities in common pathological settings. Our data also indicate that inhibition of the VDAC1 can reduce excessive fibrosis in the atrial myocardium, a finding which may have important therapeutic implications. The exact mechanism\s of this beneficial effect need further studies.

scholarly journals Identification of two voltage-dependent anion channel-like protein sequences conserved in Kinetoplastida

2012 ◽  
Vol 8 (3) ◽  
pp. 446-449 ◽  
Author(s):  
Nadine Flinner ◽  
Enrico Schleiff ◽  
Oliver Mirus
Keyword(s):  
Outer Membrane ◽  
Trypanosoma Brucei ◽  
Protein Sequences ◽  
Anion Channel ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent

The eukaryotic porin superfamily consists of two families, voltage-dependent anion channel (VDAC) and Tom40, which are both located in the mitochondrial outer membrane. In Trypanosoma brucei , only a single member of the VDAC family has been described. We report the detection of two additional eukaryotic porin-like sequences in T. brucei . By bioinformatic means, we classify both as putative VDAC isoforms.

scholarly journals TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

2016 ◽  
Vol 473 (2) ◽  
pp. 107-121 ◽  
Author(s):  
Jemma Gatliff ◽  
Michelangelo Campanella
Keyword(s):  
Neurological Diseases ◽  
Anion Channel ◽  
Translocator Protein ◽  
Endocrine Regulation ◽  
Voltage Dependent Anion Channel ◽  
Steroid Synthesis ◽  
Cellular Processes ◽  
Cellular Events ◽  
Voltage Dependent

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

Abstract 189: Activation of Voltage-Dependent Anion Channel 2 Suppresses Ca 2+ -Induced Cardiac Arrhythmia

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jaunian Chen ◽  
Johann Schredelseker ◽  
Hirohito Shimizu ◽  
Jie Huang ◽  
Kui Lu ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Cardiac Arrhythmia ◽  
Critical Role ◽  
Anion Channel ◽  
Cardiac Contraction ◽  
Voltage Dependent Anion Channel ◽  
Rescue Effect ◽  
Cardiac Fibrillation ◽  
Wide Range ◽  
Voltage Dependent

Abnormal Ca2+ handling in cardiac muscle cells is associated with a wide range of human cardiac diseases, including heart failure and cardiac arrhythmias. Zebrafish tremblor (tre) mutant embryos manifest unsynchronized cardiac contractions due to a Ca2+ extrusion defect in cardiomyocytes and thus are used as an animal model for aberrant Ca2+ homeostasis-induced cardiac arrhythmia. To further dissect molecular mechanisms regulating cardiac Ca2+ homeostasis, we conducted a chemical suppressor screen on tre and found that efsevin, a synthetic compound, potently suppresses cardiac fibrillation and restores rhythmic cardiac contractions in tre embryos. In addition, the treatment with efsevin blocks the propagation of arrhythmogenic Ca2+ waves and accelerates the decay phase of Ca2+ sparks in adult murine cardiomyocytes under Ca2+ overload conditions, demonstrating that efsevin modulates Ca2+ handling in both embryonic and adult cardiac tissues. Through a biochemical pulldown assay, we identified a direct interaction between efsevin and VDAC2, a mitochondrial outer membrane voltage dependent anion channel. Overexpression of VDAC2 restores synchronized cardiac contraction in tre and knocking down VDAC2 activity abolishes the rescue effect of efsevin on tre, suggesting that efsevin modulates cardiac Ca2+ homeostasis by potentiating VDAC2 activity. We further showed that enhancing mitochondria Ca2+ uptake by overexpressing MICU or MCU suppresses cardiac fibrillation in tre just like VDAC2 does. Interestingly, this suppressive effect is absent in tre/vdac2 double deficient embryos and co-expression of VDAC2 and MICU or MCU results in synergistic rescue effect on tre, indicating a critical role for mitochondria in regulating cardiac Ca2+ handling and rhythmicity and suggesting that VDAC2 functions as a gate for transporting Ca2+ across the outer membrane. Taken together, our findings identify efsevin as a potent pharmacological tool to modulate cardiac Ca2+ handling, suggest a critical role of mitochondria in the control of cardiac rhythmicity and establish VDAC2 as a modulator of cardiac Ca2+ handling and a potential therapeutic target for the treatment of arrhythmias.

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