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

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

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

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

Title: Lipid scramblase activity of VDAC dimers – new implications for cell death and ageing
Authors: Patrick Rockenfeller
Affiliation: Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke (UW/H), Stockumer Str. 10, 58453 Witten, Germany
Abstract: Voltage dependent anion channels (VDACs) are important proteins of the outer mitochondrial membrane (OMM). Their sophisticated beta barrel structure allows for efficient metabolite exchange between the cytosol and mitochondria. Historically VDACs had been implicated in regulated cell death as part of the so-called mitochondrial permeability transition pore (MPTP). Very recently a phospholipid scramblase activity has been attributed to VDAC dimers, which explains the manifold lipidomic changes as observed in VDAC deficient yeast strains. In this review we highlight the recent advances regarding VDAC´s phospholipid scramblase function and shed new light on VDAC´s implication in regulated cell death and ageing.

Title: To be determined
Authors: Jeff Abramson
Affiliation: David Geffen School of Medicine at UCLA., Los Angeles, United States
Abstract: Since its discovery in 1976, the voltage-dependent anion channel (VDAC) has been extensively studied both in native mitochondria and through recombinant production, unveiling numerous conserved properties. In 2008, after over 30 years since its initial identification, three independent structural projects elucidated the architecture of VDAC-1, revealing a novel class of outer membrane β-barrel proteins with an odd number of strands. The 19-stranded β-barrel structure of VDAC-1 features a hydrophobic exterior interacting with the lipid environment, while its hydrophilic interior facilitates efficient ion and metabolite passage. Notably, the negatively charged side chain of residue E73, oriented towards the hydrophobic membrane environment, likely plays a significant role in VDAC's structural integrity and functional dynamics. Further analysis of the pore interior reveals distinct distributions of charged residues along the β-strands, influencing ion conductance and selectivity. The resolved structure of VDAC-1 in its open conformation provided essential blueprints for understanding its functional mechanisms, leading to subsequent studies on ATP-bound states and variations in other VDAC isoforms. Our focus here is to compare the known VDAC structures with our newly resolved room temperature structure, emphasizing the significance of exploring alternate conformations, including the elusive closed state.