VDAC1 as a Hub Protein–Modulation of VDAC1-Mediated Prograde Cell Death, Metabolism, Inflammation and Immunity via Interacting Proteins, Metabolites and Small Molecules

Dear Colleagues,

The second installment of this Special Issue will be dedicated to honoring the groundbreaking work of Prof. Varda Shoshan-Barmatz on the mitochondrial gatekeeper VDAC1 (Voltage-Dependent Anion Channel 1). Located on the outer mitochondrial membrane (OMM), VDAC1 serves as the primary channel for the exchange of ions and metabolites between the mitochondria and the cytosol. Due to its strategic position at the crossroads between two cell spaces, it can be considered a central hub for cellular energy metabolism and bioenergetics homeostasis and for signals that modulate cell fate, including survival and death. In mammals, three VDAC isoforms (VDAC1, VDAC2, and VDAC3) have been identified, sharing some, but not all, structural and functional properties. VDAC1 is the most abundantly expressed and extensively studied, especially in tissues with high metabolic activity.

The first part of this Special Issue focused on structural and functional aspects of VDAC, highlighting new insights into its physiological and pathological roles.

(1) Shortly after its discovery, VDAC was identified as the OMM protein, characterized with respect to channel conductance, and found to be voltagein a seminal work by Marco Colombini, Roland Benz, and Dieter Bredizcka. The first protein identified as interacting with VDAC was hexokinase, observed by Daniel M. Wilson and Pedro Lowenstein in the 1970s, but the key early work widely credited with establishing this interaction is the study by Nakashima et al., 1986 (doi: 10.1021/bi00353a010). Later on, numerous groups identified VDAC as an interaction or docking site for a wide array of cytoplasmic and cytoskeletal proteins, other organelles, and even receptors on the cell surface.

To date, more than 100 proteins have been reported to interact with VDAC1, forming a complex protein–protein interaction (PPI) network that integrates mitochondrial functions into broader cellular processes. The VDAC interactome includes proteins involved in metabolism, apoptosis, signal transduction, and anti-oxidation, and DNA- and RNA-associated proteins, among others. The PPI network integrates mitochondrial functions and signaling pathways into other cellular activities, such as providing metabolites and energy for cellular functions or triggering cell death. These include metabolic enzymes such as glycerol kinase (GK), ANT (adenine nucleotide translocase), the glycolytic enzyme GAPDH (glyceraldehyde 3-phosphate dehydrogenase and hexokinase I and II (HKI/II)), the mitochondrial creatine kinase (MtCK), and CPT1a, which catalyzes the primary step of fatty acid oxidation. VDAC1 also interacts with key pro- and anti-apoptotic members of the Bcl-2 family (e.g., Bax, Bak, Bcl-2, and Bcl-xL), calcium-regulatory proteins (e.g., IP3 receptors and mitochondrial calcium uniporter), and stress- or virus-response proteins (e.g., p53, MAVS, superoxide dismutase 1, and Grp75). Cytoskeletal proteins such as gelsolin, tubulin, and actin are also part of the VDAC1 interactome.

In this second part of the Special Issue, the main focus will be on a deeper characterization of the hub function of VDAC1 and its interactors.

(2) A second theme in this Special Issue will be the interaction of VDAC with what we generically call “small molecules”. This theme was partly advanced by the identification of physiological molecules such as nucleotides that can interact with VDAC. These observations marked an inflection point in VDAC research, because, due to the absence of a classical ligand binding site, VDAC1 was long considered "undruggable". However, Prof. Varda Shoshan-Barmatz’s group changed this view, not only by demonstrating ATP, metformin, resveratrol, methyl-jesmonate, and Ca²⁺ binding to VDAC1 and characterizing their binding site but by producing the first VDAC oligomerization inhibitors: VBIT-4 and VBIT-12. Other groups, including that of Maldonado, have since contributed additional candidate compounds targeting VDAC1. The ability to modulate VDAC1 with small molecules opens up new therapeutic strategies for diseases where VDAC1 is implicated, including cancer, neurodegeneration, and metabolic disorders. The transformation of VDAC1 from an undruggable target to a therapeutically actionable target marks a significant milestone in mitochondrial biology and pharmacology.

Thus, VDAC1 appears to be a critical convergence point for diverse intracellular signals governing metabolism, cell survival, and death, which are regulated by its interaction with ligands and proteins. The articles in this Special Issue will highlight the protein’s central role as both a scaffold for protein–protein interaction and a target in small-molecule modulation. Collectively, these contributions offer valuable insights into the multifaceted biology of VDAC1 and underscore its emerging relevance as a therapeutic target. We hope that this Special Issue serves as a resource for researchers and stimulates further exploration into the translational potential of targeting VDAC1.

Sincerely,

Dr. Jay H. Chung
Prof. Dr. Vito De Pinto
Guest Editors

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