Mitochondrial Outer Membrane Voltage-Dependent Anion Channels: Unique Structures, Distinct Functions, and Novel Therapeutic Targets

Voltage-dependent anion channels (VDACs) of the outer mitochondrial membrane carry out bidirectional flux of metabolites and ions and serve as the first line of communication between the cytosol and mitochondria. They are now recognized as indispensable for mitochondrial function and cellular homeostasis, mitochondria-endoplasmic reticulum communication, lipid and cholesterol biogenesis, Ca2+ homeostasis, and mitochondria-mediated apoptosis. The unique structural features of VDACs are also important in redox regulation. VDAC dysregulation by interaction with amyloid-β, α-synuclein, Tau, or tubulin can lead to neurodegeneration. Here, we provide insights into the structures, isoform-specific molecular functions, cellular interactome, variations, and unique regulatory elements of VDACs and their direct implications for widespread burdens like cancer and neurodegeneration in humans. We discuss how deducing isoform-specific structure-function studies of VDACs has the potential for successful development of next-generation diagnostics-guided therapeutics.