A pore is a pore is a pore (or a hub?): VDAC oligomerization in mitochondrial connectivity and modulation

For decades, the voltage-dependent anion-selective channel (VDAC), formerly known as the mitochondrial porin, was considered a simple pore enabling nearly free permeability across the outer mitochondrial membrane. This simplified view has been progressively dismantled through the discovery of three mammalian isoforms (VDAC1, VDAC2, and VDAC3) with the gradual attribution, often serendipitous, of diverse cellular roles beyond passive metabolite exchange. Recent advances in cryo-electron microscopy have catalyzed a breakthrough in VDAC research. Three converging lines of evidence are reshaping our understanding: (a) high-resolution structures of VDAC within its native protein complexes; (b) discovery of unexpected functions, including phospholipid scrambling and regulation of outer membrane permeabilization through higher-order oligomeric assemblies; and (c) structural determination of VDAC interactions with macromolecules, as well as small-molecule modulators. Collectively, these insights have strengthened the consideration of VDAC as a multifunctional signaling hub and therapeutic target, with emerging small molecules and peptides designed to modulate gating, oligomerization, and interfering with interacting partners. The aim of this review is to summarize current structural, functional, and pharmacological advances in VDAC biology, emphasizing how oligomerization dynamics and isoform specificity orchestrate mitochondrial behavior and offering perspectives on therapeutic strategies for diseases driven by mitochondrial dysfunction.