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VDAC as a Cellular Hub: Docking Molecules and Interactions
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VDAC as a Cellular Hub: Docking Molecules and Interactions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 26036

Special Issue Editors

Prof. Dr. Vito De Pinto

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Guest Editor
Department of Biomedical and Biotechnological Sciences, Università di Catania, v.le A. Doria 6, 95125 Catania, Italy
Interests: pore-forming proteins; VDAC; mitochondria; bioenergetics; recombinant and mutagenised membrane protein; biophysics of membrane pores and channels
Prof. Dr. Hanna Kmita

E-Mail Website
Guest Editor
Department of Bioenergetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznan, Poland
Interests: mitochondria-mediated cytoprotection and cytotoxicity; anhydrobiosis as an anti-aging strategy; the role of VDAC in adaptation to habitat conditions
Special Issues, Collections and Topics in MDPI journals
Dr. Angela Anna Messina

E-Mail Website
Guest Editor
Department of Biological, Geological and Environmental Sciences, Section of Biochemistry and Molecular Biology, University of Catania, 95125 Catania, Italy
Interests: mitochondria; membrane proteins; bioenergetics; apoptosis; sequencing; protein–protein interaction; cell culture; recombinant protein expression
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

VDAC (voltage-dependent anion-selective channel) is the acronym that identifies the small protein channel that allows the permeability of the outer mitochondrial membrane. Unlike the selective channels of the plasma membrane, VDAC shows a hollow pore and is abundant in the OMM. Astonishing AFM micrographs have shown that the membrane is literally covered in holes, formed by VDAC. Thus, this protein also has a structural role in the membrane, since the phospholipidic surface looks more like a filter with little free space between openings rather than a continuous surface of coating.

The sequence forming the channel structure is extremely small, and much of it is involved in the formation of the walls of the channel itself. This particular organization makes binding studies and the determination of functional areas of its structure difficult. Nevertheless, the quest for molecules interacting with VDAC was undertaken simultaneously with the discovery of the pore. In 2008, the determination of the 3D structure of the pore was a breakthrough and gave to the quest of VDAC interactors a rationale. Interactions with VDAC by other molecules are beginning to be seen and areas with a specific binding role are starting to be mapped. These studies, in spite of the small size of the protein, require the deployment of technologically very advanced and highly complex approaches. Their final overall objective is to identify areas of the channel responsible for biological functions as a result of specific interactions. In this sense, we can speak of VDAC as a docking site for macromolecules, in particular those located in the cytoplasm or of cytoskeletal type. The localization of these interactions has a consequently applicative meaning, because it will allow to understand the points of this protein that may be sensitive to the action of molecules that may play a role on the overall activity of the mitochondrion and its intracellular dynamics. In practice, these studies will lead to the clear definition of that role of “Governor” of the mitochondrion that had been attributed to VDAC in a historical work. This Special Issue aims, therefore, to collect the most relevant and up-to-date information on the interactions of VDAC with physiological or designed molecules.

Prof. Dr. Vito De Pinto
Prof. Hanna Kmita
Dr. Angela Anna MESSINA
Guest Editors

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Published Papers (8 papers)

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Editorial

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3 pages, 187 KiB  
Editorial
VDAC as a Cellular Hub: Docking Molecules and Interactions
by Hanna Kmita, Angela Anna Messina and Vito De Pinto
Int. J. Mol. Sci. 2023, 24(7), 6649; https://doi.org/10.3390/ijms24076649 - 2 Apr 2023
Cited by 5 | Viewed by 1419
Abstract
The voltage-dependent anion channel (VDAC) is the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane [...] Full article
(This article belongs to the Special Issue VDAC as a Cellular Hub: Docking Molecules and Interactions)

Research

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17 pages, 3024 KiB  
Article
Targeting the Mitochondrial Protein VDAC1 as a Potential Therapeutic Strategy in ALS
by Anna Shteinfer-Kuzmine, Shirel Argueti-Ostrovsky, Marcel F. Leyton-Jaimes, Uttpal Anand, Salah Abu-Hamad, Ran Zalk, Varda Shoshan-Barmatz and Adrian Israelson
Int. J. Mol. Sci. 2022, 23(17), 9946; https://doi.org/10.3390/ijms23179946 - 1 Sep 2022
Cited by 15 | Viewed by 4068
Abstract
Impaired mitochondrial function has been proposed as a causative factor in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), caused by motor neuron degeneration. Mutations in superoxide dismutase (SOD1) cause ALS and SOD1 mutants were shown to interact with the voltage-dependent anion channel 1 [...] Read more.
Impaired mitochondrial function has been proposed as a causative factor in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), caused by motor neuron degeneration. Mutations in superoxide dismutase (SOD1) cause ALS and SOD1 mutants were shown to interact with the voltage-dependent anion channel 1 (VDAC1), affecting its normal function. VDAC1 is a multi-functional channel located at the outer mitochondrial membrane that serves as a mitochondrial gatekeeper controlling metabolic and energetic crosstalk between mitochondria and the rest of the cell and it is a key player in mitochondria-mediated apoptosis. Previously, we showed that VDAC1 interacts with SOD1 and that the VDAC1-N-terminal-derived peptide prevented mutant SOD1 cytotoxic effects. In this study, using a peptide array, we identified the SOD1 sequence that interacts with VDAC1. Synthetic peptides generated from the identified VDAC1-binding sequences in SOD1 directly interacted with purified VDAC1. We also show that VDAC1 oligomerization increased in spinal cord mitochondria isolated from mutant SOD1G93A mice and rats. Thus, we used the novel VDAC1-specific small molecules, VBIT-4 and VBIT-12, inhibiting VDAC1 oligomerization and subsequently apoptosis and associated processes such as ROS production, and increased cytosolic Ca2+. VBIT-12 was able to rescue cell death induced by mutant SOD1 in neuronal cultures. Finally, although survival was not affected, VBIT-12 administration significantly improved muscle endurance in mutant SOD1G93A mice. Therefore, VBIT-12 may represent an attractive therapy for maintaining muscle function during the progression of ALS. Full article
(This article belongs to the Special Issue VDAC as a Cellular Hub: Docking Molecules and Interactions)
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15 pages, 2324 KiB  
Article
The Open State Selectivity of the Bean Seed VDAC Depends on Stigmasterol and Ion Concentration
by Hayet Saidani, Marc Léonetti, Hanna Kmita and Fabrice Homblé
Int. J. Mol. Sci. 2021, 22(6), 3034; https://doi.org/10.3390/ijms22063034 - 16 Mar 2021
Cited by 6 | Viewed by 2117
Abstract
The voltage-dependent anion channel (VDAC) is the major pathway for metabolites and ions transport through the mitochondrial outer membrane. It can regulate the flow of solutes by switching to a low conductance state correlated with a selectivity reversal, or by a selectivity inversion [...] Read more.
The voltage-dependent anion channel (VDAC) is the major pathway for metabolites and ions transport through the mitochondrial outer membrane. It can regulate the flow of solutes by switching to a low conductance state correlated with a selectivity reversal, or by a selectivity inversion of its open state. The later one was observed in non-plant VDACs and is poorly characterized. We aim at investigating the selectivity inversion of the open state using plant VDAC purified from Phaseolus coccineus (PcVDAC) to evaluate its physiological role. Our main findings are: (1) The VDAC selectivity inversion of the open state occurs in PcVDAC, (2) Ion concentration and stigmasterol affect the occurrence of the open state selectivity inversion and stigmasterol appears to interact directly with PcVDAC. Interestingly, electrophysiological data concerning the selectivity inversion of the PcVDAC open state suggests that the phenomenon probably does not have a significant physiological effect in vivo. Full article
(This article belongs to the Special Issue VDAC as a Cellular Hub: Docking Molecules and Interactions)
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Review

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10 pages, 1238 KiB  
Review
E as in Enigma: The Mysterious Role of the Voltage-Dependent Anion Channel Glutamate E73
by Alexander Bernhard Rister, Thomas Gudermann and Johann Schredelseker
Int. J. Mol. Sci. 2023, 24(1), 269; https://doi.org/10.3390/ijms24010269 - 23 Dec 2022
Cited by 5 | Viewed by 1663
Abstract
The voltage-dependent anion channel (VDAC) is the main passageway for ions and metabolites over the outer mitochondrial membrane. It was associated with many physiological processes, including apoptosis and modulation of intracellular Ca2+ signaling. The protein is formed by a barrel of 19 [...] Read more.
The voltage-dependent anion channel (VDAC) is the main passageway for ions and metabolites over the outer mitochondrial membrane. It was associated with many physiological processes, including apoptosis and modulation of intracellular Ca2+ signaling. The protein is formed by a barrel of 19 beta-sheets with an N-terminal helix lining the inner pore. Despite its large diameter, the channel can change its selectivity for ions and metabolites based on its open state to regulate transport into and out of mitochondria. VDAC was shown to be regulated by a variety of cellular factors and molecular partners including proteins, lipids and ions. Although the physiological importance of many of these modulatory effects are well described, the binding sites for molecular partners are still largely unknown. The highly symmetrical and sleek structure of the channel makes predictions of functional moieties difficult. However, one residue repeatedly sticks out when reviewing VDAC literature. A glutamate at position 73 (E73) located on the outside of the channel facing the hydrophobic membrane environment was repeatedly proposed to be involved in channel regulation on multiple levels. Here, we review the distinct hypothesized roles of E73 and summarize the open questions around this mysterious residue. Full article
(This article belongs to the Special Issue VDAC as a Cellular Hub: Docking Molecules and Interactions)
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22 pages, 1199 KiB  
Review
VDACs Post-Translational Modifications Discovery by Mass Spectrometry: Impact on Their Hub Function
by Maria Gaetana Giovanna Pittalà, Stefano Conti Nibali, Simona Reina, Vincenzo Cunsolo, Antonella Di Francesco, Vito De Pinto, Angela Messina, Salvatore Foti and Rosaria Saletti
Int. J. Mol. Sci. 2021, 22(23), 12833; https://doi.org/10.3390/ijms222312833 - 27 Nov 2021
Cited by 10 | Viewed by 2836
Abstract
VDAC (voltage-dependent anion selective channel) proteins, also known as mitochondrial porins, are the most abundant proteins of the outer mitochondrial membrane (OMM), where they play a vital role in various cellular processes, in the regulation of metabolism, and in survival pathways. There is [...] Read more.
VDAC (voltage-dependent anion selective channel) proteins, also known as mitochondrial porins, are the most abundant proteins of the outer mitochondrial membrane (OMM), where they play a vital role in various cellular processes, in the regulation of metabolism, and in survival pathways. There is increasing consensus about their function as a cellular hub, connecting bioenergetics functions to the rest of the cell. The structural characterization of VDACs presents challenging issues due to their very high hydrophobicity, low solubility, the difficulty to separate them from other mitochondrial proteins of similar hydrophobicity and the practical impossibility to isolate each single isoform. Consequently, it is necessary to analyze them as components of a relatively complex mixture. Due to the experimental difficulties in their structural characterization, post-translational modifications (PTMs) of VDAC proteins represent a little explored field. Only in recent years, the increasing number of tools aimed at identifying and quantifying PTMs has allowed to increase our knowledge in this field and in the mechanisms that regulate functions and interactions of mitochondrial porins. In particular, the development of nano-reversed phase ultra-high performance liquid chromatography (nanoRP-UHPLC) and ultra-sensitive high-resolution mass spectrometry (HRMS) methods has played a key role in this field. The findings obtained on VDAC PTMs using such methodologies, which permitted an in-depth characterization of these very hydrophobic trans-membrane pore proteins, are summarized in this review. Full article
(This article belongs to the Special Issue VDAC as a Cellular Hub: Docking Molecules and Interactions)
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25 pages, 4876 KiB  
Review
Regulation of Mitochondrial Respiration by VDAC Is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains
by Tatiana K. Rostovtseva, Sergey M. Bezrukov and David P. Hoogerheide
Int. J. Mol. Sci. 2021, 22(14), 7358; https://doi.org/10.3390/ijms22147358 - 8 Jul 2021
Cited by 14 | Viewed by 4594
Abstract
The voltage-dependent anion channel (VDAC) is the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane. When reconstituted into lipid membranes, VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced [...] Read more.
The voltage-dependent anion channel (VDAC) is the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane. When reconstituted into lipid membranes, VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux is increased. Two otherwise unrelated cytosolic proteins, tubulin, and α-synuclein (αSyn), dock with VDAC by a novel mechanism in which the transmembrane potential draws their disordered, polyanionic C-terminal domains into and through the VDAC channel, thus physically blocking the pore. For both tubulin and αSyn, the blocked state is observed at much lower transmembrane potentials than VDAC gated states, such that in the presence of these cytosolic docking proteins, VDAC’s sensitivity to transmembrane potential is dramatically increased. Remarkably, the features of the VDAC gated states relevant for bioenergetics—reduced metabolite flux and increased calcium flux—are preserved in the blocked state induced by either docking protein. The ability of tubulin and αSyn to modulate mitochondrial potential and ATP production in vivo is now supported by many studies. The common physical origin of the interactions of both tubulin and αSyn with VDAC leads to a general model of a VDAC inhibitor, facilitates predictions of the effect of post-translational modifications of known inhibitors, and points the way toward the development of novel therapeutics targeting VDAC. Full article
(This article belongs to the Special Issue VDAC as a Cellular Hub: Docking Molecules and Interactions)
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10 pages, 552 KiB  
Review
VDAC—A Primal Perspective
by Carmen A. Mannella
Int. J. Mol. Sci. 2021, 22(4), 1685; https://doi.org/10.3390/ijms22041685 - 8 Feb 2021
Cited by 16 | Viewed by 3289
Abstract
The evolution of the eukaryotic cell from the primal endosymbiotic event involved a complex series of adaptations driven primarily by energy optimization. Transfer of genes from endosymbiont to host and concomitant expansion (by infolding) of the endosymbiont’s chemiosmotic membrane greatly increased output of [...] Read more.
The evolution of the eukaryotic cell from the primal endosymbiotic event involved a complex series of adaptations driven primarily by energy optimization. Transfer of genes from endosymbiont to host and concomitant expansion (by infolding) of the endosymbiont’s chemiosmotic membrane greatly increased output of adenosine triphosphate (ATP) and placed selective pressure on the membrane at the host–endosymbiont interface to sustain the energy advantage. It is hypothesized that critical functions at this interface (metabolite exchange, polypeptide import, barrier integrity to proteins and DNA) were managed by a precursor β-barrel protein (“pβB”) from which the voltage-dependent anion-selective channel (VDAC) descended. VDAC’s role as hub for disparate and increasingly complex processes suggests an adaptability that likely springs from a feature inherited from pβB, retained because of important advantages conferred. It is proposed that this property is the remarkable structural flexibility evidenced in VDAC’s gating mechanism, a possible origin of which is discussed. Full article
(This article belongs to the Special Issue VDAC as a Cellular Hub: Docking Molecules and Interactions)
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18 pages, 2143 KiB  
Review
A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake?
by Paulina Sander, Thomas Gudermann and Johann Schredelseker
Int. J. Mol. Sci. 2021, 22(2), 946; https://doi.org/10.3390/ijms22020946 - 19 Jan 2021
Cited by 47 | Viewed by 4201
Abstract
Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification [...] Read more.
Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification of the individual components of the mitochondrial calcium uniporter complex (MCUC) in the inner mitochondrial membrane in 2011 started a new era of research on mitochondrial Ca2+ uptake. Today, many studies investigate mitochondrial Ca2+ uptake with a strong focus on function, regulation, and localization of the MCUC. However, on its way into mitochondria Ca2+ has to pass two membranes, and the first barrier before even reaching the MCUC is the outer mitochondrial membrane (OMM). The common opinion is that the OMM is freely permeable to Ca2+. This idea is supported by the presence of a high density of voltage-dependent anion channels (VDACs) in the OMM, forming large Ca2+ permeable pores. However, several reports challenge this idea and describe VDAC as a regulated Ca2+ channel. In line with this idea is the notion that its Ca2+ selectivity depends on the open state of the channel, and its gating behavior can be modified by interaction with partner proteins, metabolites, or small synthetic molecules. Furthermore, mitochondrial Ca2+ uptake is controlled by the localization of VDAC through scaffolding proteins, which anchor VDAC to ER/SR calcium release channels. This review will discuss the possibility that VDAC serves as a physiological regulator of mitochondrial Ca2+ uptake in the OMM. Full article
(This article belongs to the Special Issue VDAC as a Cellular Hub: Docking Molecules and Interactions)
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