scholarly journals The Biogenesis Process of VDAC – From Early Cytosolic Events to Its Final Membrane Integration

2021 ◽  
Vol 12 ◽  
Author(s):  
Anasuya Moitra ◽  
Doron Rapaport
Keyword(s):  
Outer Membrane ◽  
Nuclear Dna ◽  
Current Knowledge ◽  
Yeast Cells ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent ◽  
Selective Channel ◽  
Targeting Signal ◽  
Cytosolic Factors

Voltage dependent anion-selective channel (VDAC) is the most abundant protein in the mitochondrial outer membrane. It is a membrane embedded β-barrel protein composed of 19 mostly anti-parallel β-strands that form a hydrophilic pore. Similar to the vast majority of mitochondrial proteins, VDAC is encoded by nuclear DNA, and synthesized on cytosolic ribosomes. The protein is then targeted to the mitochondria while being maintained in an import competent conformation by specific cytosolic factors. Recent studies, using yeast cells as a model system, have unearthed the long searched for mitochondrial targeting signal for VDAC and the role of cytosolic chaperones and mitochondrial import machineries in its proper biogenesis. In this review, we summarize our current knowledge regarding the early cytosolic stages of the biogenesis of VDAC molecules, the specific targeting of VDAC to the mitochondrial surface, and the subsequent integration of VDAC into the mitochondrial outer membrane by the TOM and TOB/SAM complexes.

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 C-Terminally Truncated Variant of Neurospora crassa VDAC Assembles Into a Partially Functional Form in the Mitochondrial Outer Membrane and Forms Multimers in vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Fraser G. Ferens ◽  
William A. T. Summers ◽  
Ameet Bharaj ◽  
Jörg Stetefeld ◽  
Deborah A. Court
Keyword(s):  
Neurospora Crassa ◽  
Outer Membrane ◽  
Analytical Ultracentrifugation ◽  
Size Exclusion ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent ◽  
Exclusion Chromatography ◽  
Selective Channel

The voltage-dependent anion-selective channel (VDAC) is a porin in the mitochondrial outer membrane (MOM). Unlike bacterial porins, several mitochondrial β-barrels comprise an odd number of β-strands, as is the case for the 19-β-stranded VDAC. Previously, a variant of a VDAC from Neurospora crassa, VDAC-ΔC, lacking the predicted 19th β-strand, was found to form gated, anion-selective channels in artificial membranes. In vivo, the two C-terminal β-strands (β18 and β19) in VDAC form a β-hairpin necessary for import from the cytoplasm into mitochondria and the β-signal required for assembly in the mitochondrial outer membrane resides in β19. The current study demonstrated that the putative 18-stranded β-barrel formed by VDAC-ΔC can be imported and assembled in the MOM in vivo and can also partially rescue the phenotype associated with the deletion of VDAC from a strain of N. crassa. Furthermore, when expressed and purified from Escherichia coli, VDAC-ΔC can be folded into a β-strand-rich form in decyl-maltoside. Size exclusion chromatography (SEC) alone or combined with multi-angle light scattering (SEC-MALS) and analytical ultracentrifugation revealed that, unlike full-length VDACs, VDAC-ΔC can self-organize into dimers and higher order oligomers in the absence of sterol.

Membrane integration of a mitochondrial signal-anchored protein does not require additional proteinaceous factors

2012 ◽  
Vol 442 (2) ◽  
pp. 381-389 ◽  
Author(s):  
Elisa Merklinger ◽  
Yana Gofman ◽  
Alexej Kedrov ◽  
Arnold J. M. Driessen ◽  
Nir Ben-Tal ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Lipid Bilayers ◽  
Lipid Composition ◽  
Helical Structure ◽  
Mitochondrial Outer Membrane ◽  
Artificial Lipid Bilayers ◽  
Targeting Signal ◽  
Signal Anchor ◽  
Lipid Environment ◽  
Cytosolic Factors

The MOM (mitochondrial outer membrane) contains SA (signal-anchored) proteins that bear at their N-terminus a single hydrophobic segment that serves as both a mitochondrial targeting signal and an anchor at the membrane. These proteins, like the vast majority of mitochondrial proteins, are encoded in the nucleus and have to be imported into the organelle. Currently, the mechanisms by which they are targeted to and inserted into the OM (outer membrane) are unclear. To shed light on these issues, we employed a recombinant version of the SA protein OM45 and a synthetic peptide corresponding to its signal-anchor segment. Both forms are associated with isolated mitochondria independently of cytosolic factors. Interaction with mitochondria was diminished when a mutated form of the signal-anchor was employed. We demonstrate that the signal-anchor peptide acquires an α-helical structure in a lipid environment and adopted a TM (transmembrane) topology within artificial lipid bilayers. Moreover, the peptide's affinity to artificial membranes with OM-like lipid composition was much higher than that of membranes with ER (endoplasmic reticulum)-like lipid composition. Collectively, our results suggest that SA proteins are specifically inserted into the MOM by a process that is not dependent on additional proteins, but is rather facilitated by the distinct lipid composition of this membrane.

Biogenesis pathways of α-helical mitochondrial outer membrane proteins

2020 ◽  
Vol 401 (6-7) ◽  
pp. 677-686 ◽  
Author(s):  
Layla Drwesh ◽  
Doron Rapaport
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Protein Import ◽  
Nuclear Dna ◽  
Current Knowledge ◽  
Outer Membrane Proteins ◽  
Mitochondrial Outer Membrane ◽  
Cytosolic Ribosomes

AbstractMitochondria harbor in their outer membrane (OM) proteins of different topologies. These proteins are encoded by the nuclear DNA, translated on cytosolic ribosomes and inserted into their target organelle by sophisticated protein import machineries. Recently, considerable insights have been accumulated on the insertion pathways of proteins into the mitochondrial OM. In contrast, little is known regarding the early cytosolic stages of their biogenesis. It is generally presumed that chaperones associate with these proteins following their synthesis in the cytosol, thereby keeping them in an import-competent conformation and preventing their aggregation and/or mis-folding and degradation. In this review, we outline the current knowledge about the biogenesis of different mitochondrial OM proteins with various topologies, and highlight the recent findings regarding their import pathways starting from early cytosolic events until their recognition on the mitochondrial surface that lead to their final insertion into the mitochondrial OM.

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

scholarly journals Ca2+-dependent Control of the Permeability Properties of the Mitochondrial Outer Membrane and Voltage-dependent Anion-selective Channel (VDAC)

2006 ◽  
Vol 281 (25) ◽  
pp. 17347-17358 ◽  
Author(s):  
György Báthori ◽  
György Csordás ◽  
Cecilia Garcia-Perez ◽  
Erika Davies ◽  
György Hajnóczky
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent ◽  
Selective Channel

scholarly journals The Voltage-Dependent Anion Selective Channel 1 (VDAC1) Topography in the Mitochondrial Outer Membrane as Detected in Intact Cell

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e81522 ◽  
Author(s):  
Marianna F. Tomasello ◽  
Francesca Guarino ◽  
Simona Reina ◽  
Angela Messina ◽  
Vito De Pinto
Keyword(s):  
Outer Membrane ◽  
Intact Cell ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent ◽  
Selective Channel

Molecular Design of the Voltage-Dependent, Anion-Selective Channel in the Mitochondrial Outer Membrane

1995 ◽  
Vol 114 (1) ◽  
pp. 41-59 ◽  
Author(s):  
Xiao Wei Guo ◽  
P.Ross Smith ◽  
Bernard Cognon ◽  
Dora D'Arcangelis ◽  
Elena Dolginova ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Molecular Design ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent ◽  
Selective Channel

scholarly journals Direct Membrane Insertion of Voltage-dependent Anion-selective Channel Protein Catalyzed by Mitochondrial Tom20

1999 ◽  
Vol 145 (5) ◽  
pp. 973-978 ◽  
Author(s):  
Enrico Schleiff ◽  
John R. Silvius ◽  
Gordon C. Shore
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Outer Membrane ◽  
Temperature Sensitive ◽  
Fully Integrated ◽  
Channel Protein ◽  
Transmembrane Channel ◽  
Voltage Dependent ◽  
Selective Channel ◽  
Import Receptors ◽  
Preprotein Translocation

Insertion of newly synthesized proteins into or across the mitochondrial outer membrane is initiated by import receptors at the surface of the organelle. Typically, this interaction directs the precursor protein into a preprotein translocation pore, comprised of Tom40. Here, we show that a prominent β-barrel channel protein spanning the outer membrane, human voltage- dependent anion-selective channel (VDAC), bypasses the requirement for the Tom40 translocation pore during biogenesis. Insertion of VDAC into the outer membrane is unaffected by plugging the translocation pore with a partially translocated matrix preprotein, and mitochondria containing a temperature-sensitive mutant of Tom40 insert VDAC at the nonpermissive temperature. Synthetic liposomes harboring the cytosolic domain of the human import receptor Tom20 efficiently insert newly synthesized VDAC, resulting in transbilayer transport of ATP.  Therefore, Tom20 transforms newly synthesized cytosolic VDAC into a transmembrane channel that is fully integrated into the lipid bilayer.

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