Mitochondrial Protein VDAC1 as a New Target for Novel Anti-Apoptotic Drug Development

Apoptotic signaling to the mitochondria results in the release of pro-apoptotic proteins, such as cytochrome c (Cyto c) from the mitochondrial intermembranal space to the cytosol, triggering caspases activation and apoptotic cell death. However, the mechanisms by which apoptosis activators, including Cyto c, are released from mitochondria remain unclear. The Voltage-Dependent Anion Channel 1 (VDAC1), located at the outer mitochondrial membrane, serves as a controlled passage for adenine nucleotides, Ca²⁺ and other metabolites into and out of mitochondria, as well as involved in apoptosis. Thus VDAC1 plays a crucial role in regulating the metabolic and energetic functions of mitochondria and of apoptotic cell death. Recent studies from our lab demonstrated that VDAC1 oligomerization is coupled to Cyto c release and apoptotic cell death as induced by various stimuli.

In this study, we demonstrate the inhibition of apoptosis by inhibiting VDAC1 oligomerization. Using high-throughput screening which was based on Bioluminescence Resonance Energy Transfer technology (BRET2) in living cells, several inhibitors were discovered in three rounds of screening. The effects of these small molecules on VDAC1 oligomerization were evaluated by BRET2 and chemical cross-linking. The lead compounds inhibited both apoptosis and VDAC1 oligomerization as induced by various stimuli. We also demonstrate that the compounds directly interact with purified VDAC1, as reflected in the decrease of bilayer-reconstituted VDAC1 channel conductance. The results support the suggestion that VDAC1 oligomerization is coupled to apoptosis induction.

This study revealed novel drug candidates to treat diseases associated with enhanced apoptosis with defined mechanism of action and pointing to VDAC1 as a promising target offering a therapeutic strategy for neurodegenerative diseases such as Alzheimer’s or Parkinson`s disease, where apoptosis is highly activated.