Cellular Interactome of Mitochondrial Voltage-Dependent Anion Channels: Oligomerization and Channel (Mis)Regulation

Voltage-dependent anion channels (VDACs) of the outer mitochondrial membrane are known conventionally as metabolite flux proteins. However, research findings in the past decade have revealed the multifaceted regulatory roles of VDACs, from governing cellular physiology and mitochondria-mediated apoptosis to directly regulating debilitating cancers and neurodegenerative diseases. VDACs achieve these diverse functions by establishing isoform-dependent stereospecific interactomes in the cell with the cytosolic constituents and endoplasmic reticulum complexes, and the machinery of the mitochondrial compartments. VDACs are now increasingly recognized as regulatory hubs of the cell. Not surprisingly, even the transient misregulation of VDACs results directly in mitochondrial dysfunction. Additionally, human VDACs are now implicated in interaction with aggregation-prone cytosolic proteins, including Aβ, tau, and α-synuclein, contributing directly to the onset of Alzheimer’s and Parkinson’s diseases. Deducing the interaction dynamics and mechanisms can lead to VDAC-targeted peptide-based therapeutics that can alleviate neurodegenerative states. This review succinctly presents the latest findings of the VDAC interactome, and the mode(s) of VDAC-dependent regulation of biochemical physiology. We also discuss the relevance of VDACs in pathophysiological states and aggregation-associated diseases and address how VDACs will facilitate the development of next-generation precision medicines.