Voltage-dependent anion-selective channel protein 1 (VDAC1)–Hexokinase 2 (HK2) complex (VDAC1–HK2)

The interaction between Voltage-dependent anion-selective channel protein 1 (VDAC1) and Hexokinase 2 (HK2) is a critical regulatory node in the metabolic reprogramming of cancer cells, known as the Warburg effect (Pedersen, 2008, J Bioenerg Biomembr). VDAC1, located in the outer mitochondrial membrane, serves as a gatekeeper for the exchange of metabolites between the mitochondria and the cytosol (Shoshan-Barmatz et al., 2015, Front Oncol). HK2 binds to VDAC1, gaining preferential access to mitochondrially generated ATP to accelerate glycolysis and simultaneously inhibiting the release of pro-apoptotic factors like cytochrome c (Galluzzi et al., 2008, Cell Death Differ). This interaction promotes tumor cell survival, rapid proliferation, and resistance to chemotherapy. Targeting this complex with small molecules or VDAC1-derived peptides aims to displace HK2 from the mitochondria, thereby restoring apoptotic pathways and metabolic normalcy in malignant cells (Shoshan-Barmatz et al., 2017, Oncotarget). This strategy is particularly relevant in highly glycolytic tumors where HK2 is significantly overexpressed. Disruption of the complex has been shown to reduce tumor growth and sensitize cells to standard treatments in various preclinical models. The specificity of HK2 for cancer cells compared to the HK1 isoform in normal tissues provides a potential therapeutic window for this approach.

Other names

VDAC1-HK2 interactionMitochondrial VDAC-HK2 complexHKII-VDAC1 complexHexokinase 2-VDAC1 interaction

Disruption of the protein-protein interaction (PPI) between VDAC1 and HK2, which causes the dissociation of HK2 from the outer mitochondrial membrane, leading to the inhibition of glycolysis and the induction of mitochondria-mediated apoptosis.