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 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.

scholarly journals Biogenesis of Porin of the Outer Mitochondrial Membrane Involves an Import Pathway via Receptors and the General Import Pore of the Tom Complex

2001 ◽  
Vol 152 (2) ◽  
pp. 289-300 ◽  
Author(s):  
Thomas Krimmer ◽  
Doron Rapaport ◽  
Michael T. Ryan ◽  
Chris Meisinger ◽  
C. Kenneth Kassenbrock ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Anion Channel ◽  
Mitochondrial Outer Membrane ◽  
Outer Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Surface Receptors ◽  
Voltage Dependent ◽  
Surface Receptor

Porin, also termed the voltage-dependent anion channel, is the most abundant protein of the mitochondrial outer membrane. The process of import and assembly of the protein is known to be dependent on the surface receptor Tom20, but the requirement for other mitochondrial proteins remains controversial. We have used mitochondria from Neurospora crassa and Saccharomyces cerevisiae to analyze the import pathway of porin. Import of porin into isolated mitochondria in which the outer membrane has been opened is inhibited despite similar levels of Tom20 as in intact mitochondria. A matrix-destined precursor and the porin precursor compete for the same translocation sites in both normal mitochondria and mitochondria whose surface receptors have been removed, suggesting that both precursors utilize the general import pore. Using an assay established to monitor the assembly of in vitro–imported porin into preexisting porin complexes we have shown that besides Tom20, the biogenesis of porin depends on the central receptor Tom22, as well as Tom5 and Tom7 of the general import pore complex (translocase of the outer mitochondrial membrane [TOM] core complex). The characterization of two new mutant alleles of the essential pore protein Tom40 demonstrates that the import of porin also requires a functional Tom40. Moreover, the porin precursor can be cross-linked to Tom20, Tom22, and Tom40 on its import pathway. We conclude that import of porin does not proceed through the action of Tom20 alone, but requires an intact outer membrane and involves at least four more subunits of the TOM machinery, including the general import pore.

Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function

2001 ◽  
Vol 358 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Dan GINCEL ◽  
Hilal ZAID ◽  
Varda SHOSHAN-BARMATZ
Keyword(s):  
Outer Membrane ◽  
Binding Sites ◽  
Calcium Binding ◽  
Binuclear Complex ◽  
Anion Channel ◽  
Transport Systems ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Ptp Opening

Mitochondria play a central role in energy metabolism, Ca2+ signalling, aging and cell death. To control cytosolic or mitochondrial Ca2+ concentration, mitochondria possess several Ca2+-transport systems across the inner membrane. However, the pathway for Ca2+ crossing the outer membrane has not been directly addressed. We report that purified voltage-dependent anion channel (VDAC) reconstituted into lipid bilayers or liposomes is highly permeable to Ca2+. VDAC contains Ca2+-binding sites that bind Ruthenium Red (RuR), La3+ and that RuR completely closed VDACs in single or multichannel experiments. Energized, freshly prepared mitochondria accumulate Ca2+ (500–700nmol/mg of protein), and subsequently released it. The release of Ca2+ is accompanied by cyclosporin A-inhibited swelling, suggesting activation of permeability transition pore (PTP). RuR and ruthenium amine binuclear complex, when added to mitochondria after Ca2+ accumulation has reached a maximal level and before PTP is activated, prevented the release of Ca2+ and the accompanied mitochondrial swelling. RuR also prevented PTP opening promoted by atractyloside, an adenine nucleotide translocase inhibitor. These results suggest that VDAC, located in the mitochondrial outer membrane, controls Ca2+ transport into and from the mitochondria, and that the inhibition of Ca2+ uptake by RuR and La3+ may result from their interaction with VDAC Ca2+-binding sites. Inhibition of PTP opening or assembly by RuR and ruthenium amine binuclear complex suggest the involvement of VDAC in PTP activity and/or regulation. The permeability of VDAC to Ca2+ and its binding of Ca2+, suggest that VDAC has a role in regulation of the mitochondrial Ca2+ homoeostasis.

scholarly journals Identification of new channels by systematic analysis of the mitochondrial outer membrane

2017 ◽  
Vol 216 (11) ◽  
pp. 3485-3495 ◽  
Author(s):  
Vivien Krüger ◽  
Thomas Becker ◽  
Lars Becker ◽  
Malayko Montilla-Martinez ◽  
Lars Ellenrieder ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Protein Import ◽  
Molecular Level ◽  
Anion Channel ◽  
Helical Structure ◽  
Mitochondrial Outer Membrane ◽  
Related Protein ◽  
Voltage Dependent Anion Channel ◽  
Systematic Analysis ◽  
Voltage Dependent

The mitochondrial outer membrane is essential for communication between mitochondria and the rest of the cell and facilitates the transport of metabolites, ions, and proteins. All mitochondrial outer membrane channels known to date are β-barrel membrane proteins, including the abundant voltage-dependent anion channel and the cation-preferring protein-conducting channels Tom40, Sam50, and Mdm10. We analyzed outer membrane fractions of yeast mitochondria and identified four new channel activities: two anion-preferring channels and two cation-preferring channels. We characterized the cation-preferring channels at the molecular level. The mitochondrial import component Mim1 forms a channel that is predicted to have an α-helical structure for protein import. The short-chain dehydrogenase-related protein Ayr1 forms an NADPH-regulated channel. We conclude that the mitochondrial outer membrane contains a considerably larger variety of channel-forming proteins than assumed thus far. These findings challenge the traditional view of the outer membrane as an unspecific molecular sieve and indicate a higher degree of selectivity and regulation of metabolite fluxes at the mitochondrial boundary.

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.

scholarly journals Structure of the human voltage-dependent anion channel

2008 ◽  
Vol 105 (40) ◽  
pp. 15370-15375 ◽  
Author(s):  
Monika Bayrhuber ◽  
Thomas Meins ◽  
Michael Habeck ◽  
Stefan Becker ◽  
Karin Giller ◽  
...  
Keyword(s):  
Metabolic Flux ◽  
3D Structure ◽  
Anion Channel ◽  
Bioinformatic Analysis ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
X Ray Crystallography ◽  
Voltage Dependent ◽  
Α Helix ◽  
Induced Apoptosis

The voltage-dependent anion channel (VDAC), also known as mitochondrial porin, is the most abundant protein in the mitochondrial outer membrane (MOM). VDAC is the channel known to guide the metabolic flux across the MOM and plays a key role in mitochondrially induced apoptosis. Here, we present the 3D structure of human VDAC1, which was solved conjointly by NMR spectroscopy and x-ray crystallography. Human VDAC1 (hVDAC1) adopts a β-barrel architecture composed of 19 β-strands with an α-helix located horizontally midway within the pore. Bioinformatic analysis indicates that this channel architecture is common to all VDAC proteins and is adopted by the general import pore TOM40 of mammals, which is also located in the MOM.

Moving Ca2+ from the endoplasmic reticulum to mitochondria: is spatial intimacy enough?

2006 ◽  
Vol 34 (3) ◽  
pp. 351-355 ◽  
Author(s):  
G.A. Rutter
Keyword(s):  
Endoplasmic Reticulum ◽  
Outer Membrane Proteins ◽  
Anion Channel ◽  
Mitochondrial Outer Membrane ◽  
Interconnected Network ◽  
Voltage Dependent Anion Channel ◽  
Permeabilized Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Voltage Dependent ◽  
Trisphosphate Receptor

A number of studies in recent years have demonstrated that the ER (endoplasmic reticulum) makes intimate contacts with mitochondria, the latter organelles existing both as individual organelles and occasionally as a more extensive interconnected network. Demonstrations that mitochondria take up Ca2+ more avidly upon its mobilization from the ER than when delivered to permeabilized cells as a buffered solution also indicate that a shielded conduit for Ca2+ may exist between the two organelle types, perhaps comprising the inositol 1,4,5-trisphosphate receptor and mitochondrial outer membrane proteins including the VDAC (voltage-dependent anion channel). Although the existence of such intracellular ER–mitochondria ‘synapses’, or of an ER–mitochondria Ca2+ ‘translocon’, is an exciting idea, more definitive experiments are needed to test this possibility.

Abstract 5420: Dephosphorylation of the Cardiac Mitochondrial Voltage-Dependent Anion Channel Prevents Inhibition by Hexokinase

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Qunli Cheng ◽  
Zeljko J Bosnjak ◽  
Wai-Meng Kwok
Keyword(s):  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Standard Procedure ◽  
Anion Channel ◽  
Mitochondrial Outer Membrane ◽  
Cyclophilin D ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
The Mean

The mitochondrial permeability transition pore (mPTP) has been implicated as the end effector in ischemic and pharmacological preconditioning. Though the molecular composition of the mPTP is thought to consist of cyclophilin D located in the mitochondrial matrix, adenine nucleotide translocase on the inner mitochondrial membrane, and the voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane, recent studies have raised the possibility that VDAC may be a regulatory, rather than a major, component of mPTP. Nevertheless, VDAC is likely to be a critical component of the preconditioning signaling pathway since it is the main conduit for metabolite diffusion across the mitochondrial outer membrane. Yet, the direct measurements of cardiac VDAC activity and modulation have been limited. In the present study, we purified VDAC from rat hearts using standard procedure and investigated its modulation by phosphatase and hexokinase. VDAC was incorporated into planar lipid bilayer for measurements of channel activities. The channel exhibited the reported voltage-dependent gating. Several conductance states were identified, with the most prevalent between 1.5 to 2 nS in 0.5 M NaCl. Koenig’s polyanion, a VDAC blocker, triggered channel flickering and decreased the mean current by 78±6%. In the presence of phosphatase (1 unit/ml), the mean conductance significantly increased from 1.81±0.03 to 3.68±0.61 nS (n=9; mean±SEM). However, the addition of a recombinant hexokinase (5 units/ml; GenWay Biotech) had no significant effect on the phosphatase-enhanced VDAC current (n=4). In contrast, recombinant hexokinase alone significantly decreased the mean conductance from 1.75±0.05 to 0.79±0.19 nS (n=4). The addition of phosphatase reversed the inhibitory effect of hexokinase and further enhanced VDAC activity, increasing the mean conductance to 2.69±0.19 nS (n=4). Our results suggest that the dephosphorylation of VDAC prevents the inhibitory effects of hexokinase. Furthermore, VDAC activity suppressed by hexokinase can be reversed by dephosphorylation of the channel. In conclusion, we have reported on a novel observation at the functional level that basal phosphorylation of the cardiac VDAC may be required for its modulation by hexokinase.

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