Editorial

3 pages, 187 KiB

Open AccessEditorial

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 - 02 Apr 2023

Cited by 1 | Viewed by 1014

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

Open AccessArticle

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 - 01 Sep 2022

Cited by 13 | Viewed by 3172

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 SOD1^G93A 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 SOD1^G93A 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

Open AccessArticle

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 1709

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

Open AccessReview

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 2 | Viewed by 1247

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

Open AccessReview

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 8 | Viewed by 2263

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

Open AccessReview

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 - 08 Jul 2021

Cited by 12 | Viewed by 3852

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

Open AccessReview

VDAC—A Primal Perspective

by Carmen A. Mannella

Int. J. Mol. Sci. 2021, 22(4), 1685; https://doi.org/10.3390/ijms22041685 - 08 Feb 2021

Cited by 14 | Viewed by 2816

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

Open AccessReview

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 34 | Viewed by 3513

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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