scholarly journals Arabidopsis Voltage-Dependent Anion Channels (VDACs): Overlapping and Specific Functions in Mitochondria

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1023 ◽  
Author(s):  
Mickaële Hemono ◽  
Élodie Ubrig ◽  
Kevin Azeredo ◽  
Thalia Salinas-Giegé ◽  
Laurence Drouard ◽  
...  
Keyword(s):  
Stress Response ◽  
Outer Membrane ◽  
Mitochondrial Outer Membrane ◽  
Anion Channels ◽  
Essential Components ◽  
New Knowledge ◽  
Trna Import ◽  
Voltage Dependent ◽  
Mutant Lines ◽  
Mrna Isoform

Voltage-dependent anion channels (VDACs) are essential components of the mitochondrial outer membrane. VDACs are involved in the exchange of numerous ions and molecules, from ATP to larger molecules such as tRNAs, and are supposed to adjust exchanges in response to cell signals and stresses. Four major VDACs have been identified in Arabidopsis thaliana. The goal of this study was to explore the specific functions of these proteins, in particular, in tRNA import into mitochondria and stress response. The main results were: (i) VDACs appeared to differentially interact with tRNAs, and VDAC4 could be the major tRNA channel on the outer membrane, (ii) a VDAC3 mRNA isoform was found induced by different stresses, suggesting that VDAC3 might be specifically involved in early steps of stress response and (iii) an analysis of vdac3 and vdac1 mutant lines showed that VDAC3 and VDAC1 shared some, but not all functions. In conclusion, this work brings new knowledge on VDACs, which do not appear as interchangeable pores of the outer membrane and each VDAC has its own specificity.

Role of voltage-dependent anion channels of the mitochondrial outer membrane in regulation of cell metabolism

BIOPHYSICS ◽  
2010 ◽  
Vol 55 (5) ◽  
pp. 733-739
Author(s):  
E. L. Holmuhamedov ◽  
C. Czerny ◽  
G. Lovelace ◽  
C. C. Beeson ◽  
T. Baker ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Cell Metabolism ◽  
Mitochondrial Outer Membrane ◽  
Anion Channels ◽  
Voltage Dependent

Hydroxyurea up-Regulates Voltage-Dependent Anion Channels in Human Sickle Cell Erythrocytes.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2119-2119
Author(s):  
Nick Park ◽  
Daniel Diaz ◽  
Peggy Nakagawa ◽  
Geetha Puthenveetil ◽  
Paul Gershon ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Survival ◽  
Outer Membrane ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Mitochondrial Outer Membrane ◽  
Red Cell ◽  
Anion Channels ◽  
Voltage Dependent ◽  
Red Cell Survival

Abstract Abstract 2119 Background: Hydroxyurea (HU) is clinically effective in reducing the frequency of pain crises in adults and children with sickle cell disease (SCD). In addition to increased fetal hemoglobin production, HU is known to induce macrocytosis in sickle cell erythrocytes and prolong red cell survival. However, the precise mechanism by which HU produces its varied effects is unknown. Isoelectric focusing has been applied to characterize changes in the red cell membrane following exposure to HU, but this technique has limitations in its ability to identify differences in specific membrane proteins. Mass spectrometry (MS) provides another proteomic approach in analyzing red cell proteins in SCD. Methods: Red blood cells were obtained from patients with SCD on HU therapy. After multiple wash and lysis steps, ghost membranes were obtained following ultracentrifugation. The membrane samples were then analyzed via tandem mass spectrometry and western immunoblot assay. Results: In comparison to a normal control, patients with SCD on HU therapy were found to have significantly elevated levels of voltage-dependent anion channels (VDAC) by MS, using a false discovery rate of less than five percent. The application of a stringent threshold initially identified 346 protein candidates. Out of these 346 proteins, 125 contained multiple peptides which all passed quantitation data filters according to quality parameters. Within the set of 125 proteins, 4 proteins were significantly up-regulated (up to 50-fold) in patients with SCD on HU therapy. VDAC2 and VDAC3 are members of the eukaryotic mitochondrial porin family which form channels through the mitochondrial outer membrane allowing diffusion of small hydrophilic molecules. VDAC1 can be found in both the mitochondrial outer membrane and the plasma membrane, where it is involved in cell volume regulation and apoptosis. Conclusions: Up-regulation of VDAC proteins may play an important role in altering the intracellular osmotic composition of the sickle cell erythrocyte resulting in decreased sickling and improved red cell survival in patients with SCD on HU therapy. Disclosures: No relevant conflicts of interest to declare.

Cryo-Electron Microscopy and Correlation Averaging of Frozen-Hydrated, Polymorphic 2D Crystals of the Mitochondrial Outer Membrane Channel

1990 ◽  
Vol 48 (1) ◽  
pp. 100-101
Author(s):  
Xiao-Wei Guo
Keyword(s):  
Outer Membrane ◽  
Hexagonal Lattice ◽  
Mitochondrial Outer Membrane ◽  
Rectangular Lattice ◽  
Electron Microscopic ◽  
Cryo Electron Microscopy ◽  
Voltage Dependent ◽  
Outer Membrane Channel ◽  
2D Crystals ◽  
Vdac Channel

Voltage-dependent, anion-selective channels (VDAC) are formed in the mitochondrial outer membrane (mitOM) by a 30-kDa polypeptide. These channels form ordered 2D arrays when mitOMs from Neurospora crassa are treated with soluble phospholipase A2. We obtain low-dose electron microscopic images of unstained specimens of VDAC crystals preserved in vitreous ice, using a Philips EM420 equipped with a Gatan cryo-transfer stage. We then use correlation analysis to compute average projections of the channel crystals. The procedure involves Fourier-filtration of a region within a crystal field to obtain a preliminary average that is subsequently cross-correlated with the entire crystal. Subregions are windowed from the crystal image at coordinates of peaks in the cross-correlation function (CCF, see Figures 1 and 2) and summed to form averages (Figure 3).The VDAC channel forms several different types of crystalline arrays in mitOMs. The polymorph first observed during phospholipase treatment is a parallelogram array (a=13 run, b=11.5 run, θ==109°) containing 6 water-filled pores per unit cell. Figure 1 shows the CCF of a sub-field of such an “oblique” array used to compute the correlation average of Figure 3A. With increased phospholipase treatment, other polymorphs are observed, often co-existing within the same crystal. For example, two distinct (but closely related) types of lattices occur in the field corresponding to the CCF of Figure 2: a “contracted” version of the parallelogram lattice (a=13 run, b=10 run, θ=99°), and a near-rectangular lattice (a=8.5 run, b=5 nm). The pattern of maxima in this CCF suggests that a third, near-hexagonal lattice (a=4.5 nm) may also be present. The correlation averages of Figures 3B-D were computed from polycrystalline fields, using peak coordinates in regions of CCFs corresponding to each of the three lattice types.

Effects of cytochrome c on the mitochondrial apoptosis-induced channel MAC

2004 ◽  
Vol 286 (5) ◽  
pp. C1109-C1117 ◽  
Author(s):  
Liang Guo ◽  
Dawn Pietkiewicz ◽  
Evgeny V. Pavlov ◽  
Sergey M. Grigoriev ◽  
John J. Kasianowicz ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Outer Membrane ◽  
Cell Types ◽  
Rnase A ◽  
Mitochondrial Outer Membrane ◽  
Dependent Manner ◽  
Mitochondrial Apoptosis ◽  
Noise Type ◽  
Voltage Dependent

Recent studies indicate that cytochrome c is released early in apoptosis without loss of integrity of the mitochondrial outer membrane in some cell types. The high-conductance mitochondrial apoptosis-induced channel (MAC) forms in the outer membrane early in apoptosis of FL5.12 cells. Physiological (micromolar) levels of cytochrome c alter MAC activity, and these effects are referred to as types 1 and 2. Type 1 effects are consistent with a partitioning of cytochrome c into the pore of MAC and include a modest decrease in conductance that is dose and voltage dependent, reversible, and has an increase in noise. Type 2 effects may correspond to “plugging” of the pore or destabilization of the open state. Type 2 effects are a dose-dependent, voltage-independent, and irreversible decrease in conductance. MAC is a heterogeneous channel with variable conductance. Cytochrome c affects MAC in a pore size-dependent manner, with maximal effects of cytochrome c on MAC with conductance of 1.9–5.4 nS. The effects of cytochrome c, RNase A, and high salt on MAC indicate that size, rather than charge, is crucial. The effects of dextran molecules of various sizes indicate that the pore diameter of MAC is slightly larger than that of 17-kDa dextran, which should be sufficient to allow the passage of 12-kDa cytochrome c. These findings are consistent with the notion that MAC is the pore through which cytochrome c is released from mitochondria during apoptosis.

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.

Origami in the outer membrane: the transmembrane arrangement of mitochondrial porins

2002 ◽  
Vol 80 (5) ◽  
pp. 551-562 ◽  
Author(s):  
Denice C Bay ◽  
Deborah A Court
Keyword(s):  
Outer Membrane ◽  
Structural Information ◽  
Mitochondrial Outer Membrane ◽  
Wild Type ◽  
Mitochondrial Porin ◽  
Electrophysiological Properties ◽  
Common Structure ◽  
Outer Membrane Porins ◽  
Voltage Dependent ◽  
Bacterial Porins

Voltage-dependent anion-selective channels (VDAC), also known as mitochondrial porins, are key regulators of metabolite flow across the mitochondrial outer membrane. Porins from a wide variety of organisms share remarkably similar electrophysiological properties, in spite of considerable sequence dissimilarity, indicating that they share a common structure. Based on primary sequence considerations, analogy with bacterial porins, and circular dichroism analysis, it is agreed that VDAC spans the outer membrane as a β-barrel. However, the residues that form the antiparallel β-strands comprising this barrel remain unknown. Various predictive methods, largely based on the known structures of bacterial β-barrels, have been applied to the primary sequences of VDAC. Refinement and confirmation of these predictions have developed through numerous investigations of wild-type and variant porins, both in mitochondria and in artificial membranes. These experiments have involved VDAC from several sources, precluding the generation of a unified model. Herein, using the Neurospora VDAC sequence as a template, the published structural information and predictions have been reassessed to delineate a model that satisfies most of the available data.Key words: VDAC, mitochondrial porin, β-barrel.

Phosphorothioate oligonucleotides reduce mitochondrial outer membrane permeability to ADP

2007 ◽  
Vol 292 (4) ◽  
pp. C1388-C1397 ◽  
Author(s):  
Wenzhi Tan ◽  
Johnathan C. Lai ◽  
Paul Miller ◽  
C. A. Stein ◽  
Marco Colombini
Keyword(s):  
Cytochrome C ◽  
Membrane Permeability ◽  
Outer Membrane ◽  
Mitochondrial Outer Membrane ◽  
Cytochrome C Release ◽  
Voltage Dependent ◽  
Selective Channel ◽  
Vdac Channels ◽  
Outer Membrane Permeability ◽  
Apoptotic Cascade

G3139, an antisense Bcl-2 phosphorothioate oligodeoxyribonucleotide, induces apoptosis in melanoma and other cancer cells. This apoptosis happens before and in the absence of the downregulation of Bcl-2 and thus seems to be Bcl-2-independent. Binding of G3139 to mitochondria and its ability to close voltage-dependent anion-selective channel (VDAC) have led to the hypothesis that G3139 acts, in part, by interacting with VDAC channels in the mitochondrial outer membrane ( 21 ). In this study, we demonstrate that G3139 is able to reduce the mitochondrial outer membrane permeability to ADP by a factor of 6 or 7 with a Ki between 0.2 and 0.5 μM. Because VDAC is responsible for this permeability, this result strengthens the aforesaid hypothesis. Other mitochondrial respiration components are not affected by [G3139] up to 1 μM. Higher levels begin to inhibit respiration rates, decrease light scattering and increase uncoupled respiration. These results agree with accumulating evidence that VDAC closure favors cytochrome c release. The speed of this effect (within 10 min) places it early in the apoptotic cascade with cytochrome c release occurring at later times. Other phosphorothioate oligonucleotides are also able to induce VDAC closure, and there is some length dependence. The phosphorothioate linkages are required to induce the reduction of outer membrane permeability. At levels below 1 μM, phosphorothioate oligonucleotides are the first specific tools to restrict mitochondrial outer membrane permeability.

scholarly journals A Stress Response Monitoring Lipoprotein Trafficking to the Outer Membrane

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Kerrie L. May ◽  
Kelly M. Lehman ◽  
Angela M. Mitchell ◽  
Marcin Grabowicz
Keyword(s):  
Escherichia Coli ◽  
Stress Response ◽  
Outer Membrane ◽  
Stress Responses ◽  
Stress System ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Content Type ◽  
Essential Components ◽  
Trafficking Defects

ABSTRACTGram-negative bacteria produce lipid-anchored lipoproteins that are trafficked to their outer membrane (OM). These lipoproteins are essential components in each of the molecular machines that build the OM, including the Bam machine that assembles β-barrel proteins and the Lpt pathway that transports lipopolysaccharide. Stress responses are known to monitor Bam and Lpt function, yet no stress system has been found that oversees the fundamental process of lipoprotein trafficking. We used genetic and chemical biology approaches to induce several different lipoprotein trafficking stresses inEscherichia coli. Our results identified the Cpx two-component system as a stress response for monitoring trafficking. Cpx is activated by trafficking defects and is required to protect the cell against the consequence of the resulting stress. The OM-targeted lipoprotein NlpE acts as a sensor that allows Cpx to gauge trafficking efficiency. We reveal that NlpE signals to Cpx while it is transiting the inner membrane (IM)en routeto the OM and that only a small highly conserved N-terminal domain is required for signaling. We propose that defective trafficking causes NlpE to accumulate in the IM, activating Cpx to mount a transcriptional response that protects cells. Furthermore, we reconcile this new role of NlpE in signaling trafficking defects with its previously proposed role in sensing copper (Cu) stress by demonstrating that Cu impairs acylation of lipoproteins and, consequently, their trafficking to the OM.IMPORTANCEThe outer membrane built by Gram-negative bacteria such asEscherichia coliforms a barrier that prevents antibiotics from entering the cell, limiting clinical options at a time of prevalent antibiotic resistance. Stress responses ensure that barrier integrity is continuously maintained. We have identified the Cpx signal transduction system as a stress response that monitors the trafficking of lipid-anchored lipoproteins to the outer membrane. These lipoproteins are needed by every machine that builds the outer membrane. Cpx monitors just one lipoprotein, NlpE, to detect the efficiency of lipoprotein trafficking in the cell. NlpE and Cpx were previously shown to play a role in resistance to copper. We show that copper blocks lipoprotein trafficking, reconciling old and new observations. Copper is an important element in innate immunity against pathogens, and our findings suggest that NlpE and Cpx helpE. colisurvive the assault of copper on a key outer membrane assembly pathway.

scholarly journals VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease

Science ◽  
2019 ◽  
Vol 366 (6472) ◽  
pp. 1531-1536 ◽  
Author(s):  
Jeonghan Kim ◽  
Rajeev Gupta ◽  
Luz P. Blanco ◽  
Shutong Yang ◽  
Anna Shteinfer-Kuzmine ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Lupus Erythematosus ◽  
Anion Channel ◽  
Live Cells ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Extracellular Traps ◽  
Voltage Dependent ◽  
Positively Charged

Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type Ι interferon (IFN) response. Mitochondrial outer membrane permeabilization, which is required for mtDNA release, has been extensively studied in apoptotic cells, but little is known about its role in live cells. We found that oxidatively stressed mitochondria release short mtDNA fragments via pores formed by the voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane. Furthermore, the positively charged residues in the N-terminal domain of VDAC1 interact with mtDNA, promoting VDAC1 oligomerization. The VDAC oligomerization inhibitor VBIT-4 decreases mtDNA release, IFN signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. Thus, inhibiting VDAC oligomerization is a potential therapeutic approach for diseases associated with mtDNA release.

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