Voltage-dependent anion-selective channel (VDAC)

The Voltage-dependent anion-selective channel (VDAC) is a pore-forming protein located in the outer mitochondrial membrane (OMM), serving as the primary gatekeeper for the exchange of metabolites and ions between the mitochondria and the cytosol [3, 6]. It exists in three mammalian isoforms (VDAC1, VDAC2, and VDAC3), with VDAC1 being the most abundant and extensively studied as a therapeutic target [12, 16]. VDAC plays a dual role in cell life and death: it facilitates the transport of ATP, ADP, and calcium to support cellular bioenergetics, while its oligomerization and interaction with pro-apoptotic proteins trigger the release of cytochrome c to initiate apoptosis [4, 13]. In cancer, VDAC is often overexpressed and associated with anti-apoptotic proteins like hexokinase, promoting tumor survival and metabolic reprogramming [10, 16]. Conversely, its dysfunction is linked to neurodegenerative diseases such as Alzheimer's and Parkinson's, where it contributes to mitochondrial impairment and excessive cell death [11, 13]. Therapeutic strategies involve small molecules and peptides that either induce apoptosis in cancer cells by disrupting VDAC-protein complexes or protect neurons by stabilizing VDAC function [4, 11].

Other names

Mitochondrial porinPorin 31HLVDAC1VDAC2VDAC3Outer mitochondrial membrane protein porin

Drugs targeting VDAC typically act by modulating its channel conductance between open and closed states, inhibiting its oligomerization to prevent the formation of large pores that release pro-apoptotic factors, or disrupting its interaction with anti-apoptotic proteins like hexokinase and Bcl-2 to promote cell death in cancer cells [4, 9, 11]. Some compounds, such as Erastin, bind to VDAC to induce oxidative stress and ferroptosis [11].