VDAC1 as a player in mitochondria-mediated apoptosis and target for modulating apoptosis.

Background: The voltage-dependent anion channel 1 (VDAC1), an outer mitochondria membrane protein, functions as a mitochondrial governor, controlling transport of metabolites in and out of the mitochondria and energy production, while also coordinating glycolysis and oxidative phosphorylation. VDAC1 plays a key role in mitochondria-mediated apoptosis by functioning in the release of apoptotic proteins located in the inter-membranal space and due to its association with pro- and anti-apoptotic proteins. Thus, VDAC1 is considered as a promising target for controlling apoptosis. Methods: We reviewed published data presenting accumulated evidence suggesting that VDAC1 oligomerization represents an important step in the intrinsic mitochondria-mediated apoptosis pathway. Results: The published data support the proposal that VDAC1 oligomerization leads to the formation of a large pore that allows the release of pro-apoptotic proteins to the cytosol, thereby, activation of apoptosis. Evidence for the relationship between VDAC1 expression levels and induction of apoptosis are presented. This includes the finding that almost all apoptosis stimuli induce VDAC1 over-expression shifting VDAC1 from a monomeric to an oligomeric assembly, corresponding to the Cyto c release channel. Copounds or conditions inducing VDAC1 over-expression, VDAC1 oligomerization and apoptosis are presented. Likewise, VDAC1-interacting molecules, that inhibit both VDAC1 oligomerization and apoptosis are also presented. Conclusion: This review highlights the findings about VDAC1 oligomerization as a potential target for controlling apoptosis, specifically using drugs to induce apoptotic cell death in cancer and inhibit apoptosis in neurodegenerative diseases, as well as possible VDAC1-based therapeutic applications.