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The Central Role of Mitochondrial Protein VDAC1 in Human Diseases...
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The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 7865

Special Issue Editor

Prof. Dr. Jay H. Chung

E-Mail Website
Guest Editor
Laboratory of Obesity and Aging Research, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892-1412, USA
Interests: mitochondria; VDAC, inflammation; aging; obesity; autoimmune disease; reactive oxygen species; autophagy; cancer; fatty liver

Special Issue Information

Dear Colleagues,

The discovery of the voltage-dependent anion channel (VDAC) within the mitochondrial membrane traces back to the mid-1970s. Although the biological implications of VDAC were unclear at the time, subsequent research revealed that it is the gatekeeper of mitochondrial function and serves as a nexus for many metabolic processes. When faced with stressful conditions, VDAC can undergo oligomerization and disrupt mitochondrial integrity, though the precise architecture of VDAC oligomers remains somewhat elusive. In the realm of VDAC research, numerous pioneers have made significant contributions, yet Prof. Varda Shoshan-Barmatz is at the forefront in understanding how VDAC1 governs mitochondrial function and dysfunction, particularly how its overexpression and oligomerization mediate apoptosis and inflammation, and thus contributing to a spectrum of diseases ranging from cancer to Alzheimer’s disease.

Prof. Shoshan-Barmatz’s group demonstrated that induction of apoptosis leads to VDAC1 overexpression and oligomerization, forming a large channel allowing pro-apoptotic protein release and subsequent apoptosis. Oligomeric VDAC1 is also at the nexus of mitochondria DNA (mtDNA) release into the cytosol triggering type-Ι interferon signaling and inflammation. Moreover, her group and others have demonstrated that overexpression of VDAC1 may contribute to type-2 diabetes, as well as neurodegenerative, cardiac, and autoimmune diseases.

Considering the potential of VDAC1 as a novel target for regulating cell metabolism, inflammation, and programmed cell death across a spectrum of diseases, Prof. Shoshan-Barmatz developed new VDAC1-interacting molecules, VBIT-4 and VBIT-12. These molecules prevent VDAC1 oligomerization, cell death, mitochondrial dysfunction, and inflammation, offering hope for improved treatments in a variety of medical conditions. Thus, for this honorary Special Issue commemorating the work of Prof. Varda Shoshan-Barmatz, we invite the submission of papers related to VDAC function in metabolic cross-talk between the mitochondria and the rest of the cell, energy production and metabolism, Ca2+ homeostasis, apoptosis, protein interactions, and regulation of mitochondrial functions in health and disease.

Dr. Jay H. Chung
Guest Editor

Manuscript Submission Information

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Keywords

  • apoptosis
  • ferroptosis
  • inflammation
  • metabolism
  • mitochondria
  • oxidative stress
  • pyroptosis
  • VDAC
  • cancer

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Published Papers (6 papers)

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Research

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10 pages, 3601 KiB  
Article
Insights into VDAC Gating: Room-Temperature X-ray Crystal Structure of mVDAC-1
by Kristofer R. Gonzalez-DeWhitt, Natalia Ermolova, Harrison K. Wang, Doeke R. Hekstra, Thorsten Althoff and Jeff Abramson
Biomolecules 2024, 14(10), 1203; https://doi.org/10.3390/biom14101203 - 24 Sep 2024
Viewed by 880
Abstract
The voltage-dependent anion channel (VDAC) is a crucial mitochondrial protein that facilitates ion and metabolite exchange between mitochondria and the cytosol. Initially characterized over three decades ago, the structure of VDAC-1 was resolved in 2008, revealing a novel β-barrel protein architecture. This study [...] Read more.
The voltage-dependent anion channel (VDAC) is a crucial mitochondrial protein that facilitates ion and metabolite exchange between mitochondria and the cytosol. Initially characterized over three decades ago, the structure of VDAC-1 was resolved in 2008, revealing a novel β-barrel protein architecture. This study presents the first room-temperature crystal structure of mouse VDAC-1 (mVDAC-1), which is a significant step toward understanding the channel’s gating mechanism. The new structure, obtained at a 3.3 Å resolution, demonstrates notable differences from the previously determined cryogenic structure, particularly in the loop regions, which may be critical for the transition between the ‘open’ and ‘closed’ states of VDAC-1. Comparative analysis of the root-mean-square deviation (R.M.S.D.) and B-factors between the cryogenic and room-temperature structures suggests that these conformational differences, although subtle, are important for VDAC’s functional transitions. The application of electric field-stimulated X-ray crystallography (EF-X) is proposed as a future direction to resolve the ‘closed’ state of VDAC-1 by inducing voltage-driven conformational changes in order to elucidate the dynamic gating mechanism of VDAC-1. Our findings have profound implications for understanding the molecular basis of VDAC’s role in mitochondrial function and its regulation under physiological conditions. Full article
(This article belongs to the Special Issue The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz)
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Review

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28 pages, 3458 KiB  
Review
Decoding Cancer through Silencing the Mitochondrial Gatekeeper VDAC1
by Tasleem Arif, Anna Shteinfer-Kuzmine and Varda Shoshan-Barmatz
Biomolecules 2024, 14(10), 1304; https://doi.org/10.3390/biom14101304 - 15 Oct 2024
Viewed by 1173
Abstract
Mitochondria serve as central hubs for regulating numerous cellular processes that include metabolism, apoptosis, cell cycle progression, proliferation, differentiation, epigenetics, immune signaling, and aging. The voltage-dependent anion channel 1 (VDAC1) functions as a crucial mitochondrial gatekeeper, controlling the flow of ions, such as [...] Read more.
Mitochondria serve as central hubs for regulating numerous cellular processes that include metabolism, apoptosis, cell cycle progression, proliferation, differentiation, epigenetics, immune signaling, and aging. The voltage-dependent anion channel 1 (VDAC1) functions as a crucial mitochondrial gatekeeper, controlling the flow of ions, such as Ca2+, nucleotides, and metabolites across the outer mitochondrial membrane, and is also integral to mitochondria-mediated apoptosis. VDAC1 functions in regulating ATP production, Ca2+ homeostasis, and apoptosis, which are essential for maintaining mitochondrial function and overall cellular health. Most cancer cells undergo metabolic reprogramming, often referred to as the “Warburg effect”, supplying tumors with energy and precursors for the biosynthesis of nucleic acids, phospholipids, fatty acids, cholesterol, and porphyrins. Given its multifunctional nature and overexpression in many cancers, VDAC1 presents an attractive target for therapeutic intervention. Our research has demonstrated that silencing VDAC1 expression using specific siRNA in various tumor types leads to a metabolic rewiring of the malignant cancer phenotype. This results in a reversal of oncogenic properties that include reduced tumor growth, invasiveness, stemness, epithelial–mesenchymal transition. Additionally, VDAC1 depletion alters the tumor microenvironment by reducing angiogenesis and modifying the expression of extracellular matrix- and structure-related genes, such as collagens and glycoproteins. Furthermore, VDAC1 depletion affects several epigenetic-related enzymes and substrates, including the acetylation-related enzymes SIRT1, SIRT6, and HDAC2, which in turn modify the acetylation and methylation profiles of histone 3 and histone 4. These epigenetic changes can explain the altered expression levels of approximately 4000 genes that are associated with reversing cancer cells oncogenic properties. Given VDAC1’s critical role in regulating metabolic and energy processes, targeting it offers a promising strategy for anti-cancer therapy. We also highlight the role of VDAC1 expression in various disease pathologies, including cardiovascular, neurodegenerative, and viral and bacterial infections, as explored through siRNA targeting VDAC1. Thus, this review underscores the potential of targeting VDAC1 as a strategy for addressing high-energy-demand cancers. By thoroughly understanding VDAC1’s diverse roles in metabolism, energy regulation, mitochondrial functions, and other cellular processes, silencing VDAC1 emerges as a novel and strategic approach to combat cancer. Full article
(This article belongs to the Special Issue The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz)
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12 pages, 965 KiB  
Review
Voltage-Dependent Anion Channels in Male Reproductive Cells: Players in Healthy Fertility?
by Stefano Conti Nibali, Giuseppe Battiato, Xena Giada Pappalardo and Vito De Pinto
Biomolecules 2024, 14(10), 1290; https://doi.org/10.3390/biom14101290 - 12 Oct 2024
Viewed by 1320
Abstract
Male infertility affects nearly 50% of infertile couples, with various underlying causes, including endocrine disorders, testicular defects, and environmental factors. Spermatozoa rely on mitochondrial oxidative metabolism for motility and fertilization, with mitochondria playing a crucial role in sperm energy production, calcium regulation, and [...] Read more.
Male infertility affects nearly 50% of infertile couples, with various underlying causes, including endocrine disorders, testicular defects, and environmental factors. Spermatozoa rely on mitochondrial oxidative metabolism for motility and fertilization, with mitochondria playing a crucial role in sperm energy production, calcium regulation, and redox balance. Voltage-dependent anion channels (VDACs), located on the outer mitochondrial membrane, regulate energy and metabolite exchange, which are essential for sperm function. This review offers an updated analysis of VDACs in the male reproductive system, summarizing recent advances in understanding their expression patterns, molecular functions, and regulatory mechanisms. Although VDACs have been widely studied in other tissues, their specific roles in male reproductive physiology still remain underexplored. Special attention is given to the involvement of VDAC2/3 isoforms, which may influence mitochondrial function in sperm cells and could be implicated in male fertility disorders. This update provides a comprehensive framework for future research in reproductive biology, underscoring the significance of VDACs as a molecular link between mitochondrial function and male fertility. Full article
(This article belongs to the Special Issue The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz)
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13 pages, 3426 KiB  
Review
Phospholipid Scramblase Activity of VDAC Dimers: New Implications for Cell Death, Autophagy and Ageing
by Patrick Rockenfeller
Biomolecules 2024, 14(10), 1218; https://doi.org/10.3390/biom14101218 - 26 Sep 2024
Viewed by 772
Abstract
Voltage-dependent anion channels (VDACs) are important proteins of the outer mitochondrial membrane (OMM). Their beta-barrel structure allows for efficient metabolite exchange between the cytosol and mitochondria. VDACs have further been implicated in the control of regulated cell death. Historically, VDACs have been pictured [...] Read more.
Voltage-dependent anion channels (VDACs) are important proteins of the outer mitochondrial membrane (OMM). Their beta-barrel structure allows for efficient metabolite exchange between the cytosol and mitochondria. VDACs have further been implicated in the control of regulated cell death. Historically, VDACs have been pictured as part of the mitochondrial permeability transition pore (MPTP). New concepts of regulated cell death involving VDACs include its oligomerisation to form a large pore complex in the OMM; however, alternative VDAC localisation to the plasma membrane has been suggested in the literature and will be discussed regarding its potential role during cell death. Very recently, a phospholipid scramblase activity has been attributed to VDAC dimers, which explains the manifold lipidomic changes observed in VDAC-deficient yeast strains. In this review, I highlight the recent advances regarding VDAC’s phospholipid scramblase function and discuss how this new insight sheds new light on VDAC’s implication in regulated cell death, autophagy, and ageing. Full article
(This article belongs to the Special Issue The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz)
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21 pages, 4641 KiB  
Review
VDAC1-Based Peptides as Potential Modulators of VDAC1 Interactions with Its Partners and as a Therapeutic for Cancer, NASH, and Diabetes
by Anna Shteinfer-Kuzmine, Manikandan Santhanam and Varda Shoshan-Barmatz
Biomolecules 2024, 14(9), 1139; https://doi.org/10.3390/biom14091139 - 9 Sep 2024
Viewed by 1384
Abstract
This review presents current knowledge related to the voltage-dependent anion channel-1 (VDAC1) as a multi-functional mitochondrial protein that acts in regulating both cell life and death. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows control of metabolic cross-talk between the [...] Read more.
This review presents current knowledge related to the voltage-dependent anion channel-1 (VDAC1) as a multi-functional mitochondrial protein that acts in regulating both cell life and death. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows control of metabolic cross-talk between the mitochondria and the rest of the cell, and also enables its interaction with proteins that are involved in metabolic, cell death, and survival pathways. VDAC1′s interactions with over 150 proteins can mediate and regulate the integration of mitochondrial functions with cellular activities. To target these protein–protein interactions, VDAC1-derived peptides have been developed. This review focuses specifically on cell-penetrating VDAC1-based peptides that were developed and used as a “decoy” to compete with VDAC1 for its VDAC1-interacting proteins. These peptides interfere with VDAC1 interactions, for example, with metabolism-associated proteins such as hexokinase (HK), or with anti-apoptotic proteins such as Bcl-2 and Bcl-xL. These and other VDAC1-interacting proteins are highly expressed in many cancers. The VDAC1-based peptides in cells in culture selectively affect cancerous, but not non-cancerous cells, inducing cell death in a variety of cancers, regardless of the cancer origin or genetics. They inhibit cell energy production, eliminate cancer stem cells, and act very rapidly and at low micro-molar concentrations. The activity of these peptides has been validated in several mouse cancer models of glioblastoma, lung, and breast cancers. Their anti-cancer activity involves a multi-pronged attack targeting the hallmarks of cancer. They were also found to be effective in treating non-alcoholic fatty liver disease and diabetes mellitus. Thus, VDAC1-based peptides, by targeting VDAC1-interacting proteins, offer an affordable and innovative new conceptual therapeutic paradigm that can potentially overcome heterogeneity, chemoresistance, and invasive metastatic formation. Full article
(This article belongs to the Special Issue The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz)
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17 pages, 1731 KiB  
Review
VDAC in Retinal Health and Disease
by Ying Xu, Shanti R. Tummala, Xiongmin Chen and Noga Vardi
Biomolecules 2024, 14(6), 654; https://doi.org/10.3390/biom14060654 - 4 Jun 2024
Viewed by 1352
Abstract
The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further processed before they are sent to the brain to be interpreted as images. The retina is [...] Read more.
The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further processed before they are sent to the brain to be interpreted as images. The retina is unique in that it is continuously exposed to light and has the highest metabolic rate and demand for energy amongst all the tissues in the body. Consequently, the retina is very susceptible to oxidative stress. VDAC, a pore in the outer membrane of mitochondria, shuttles metabolites between mitochondria and the cytosol and normally protects cells from oxidative damage, but when a cell’s integrity is greatly compromised it initiates cell death. There are three isoforms of VDAC, and existing evidence indicates that all three are expressed in the retina. However, their precise localization and function in each cell type is unknown. It appears that most retinal cells express substantial amounts of VDAC2 and VDAC3, presumably to protect them from oxidative stress. Photoreceptors express VDAC2, HK2, and PKM2—key proteins in the Warburg pathway that also protect these cells. Consistent with its role in initiating cell death, VDAC is overexpressed in the retinal degenerative diseases retinitis pigmentosa, age related macular degeneration (AMD), and glaucoma. Treatment with antioxidants or inhibiting VDAC oligomerization reduced its expression and improved cell survival. Thus, VDAC may be a promising therapeutic candidate for the treatment of these diseases. Full article
(This article belongs to the Special Issue The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: VDAC structure, function, and regulation
Author: Rostovtseva
Highlights: Review paper

Title: To be determined
Authors: Ralf Paus; Jeremy Cheret
Affiliation: The University of Manchester, Manchester, United Kingdom

Title: VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration
Authors: Adrian Israelson
Affiliation: Ben-Gurion University of the Negev, Beer Sheba, Israel

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