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

The Hexokinase 2–Voltage-dependent anion-selective channel protein 1 (HK2–VDAC1) interface is a critical regulatory site in the metabolic reprogramming of cancer cells, known as the Warburg effect (Pedersen, 2008, J. Bioenerg. Biomembr.). Hexokinase 2 (HK2) is frequently overexpressed in malignant tumors and translocates to the outer mitochondrial membrane, where it binds to VDAC1 (Shoshan-Barmatz et al., 2015, Front. Oncol.). This interaction provides HK2 with direct access to mitochondrially generated ATP, accelerating glycolysis and providing a survival advantage (Mathupala et al., 2006, Oncogene). Furthermore, the binding of HK2 to VDAC1 prevents the recruitment of pro-apoptotic proteins like Bax, thereby inhibiting the release of cytochrome c and suppressing apoptosis (Abu-Hamad et al., 2008, J. Cell Sci.). Targeting this interface with small molecules or mimetic peptides aims to detach HK2 from the mitochondria, simultaneously crippling the cell's energy production and restoring apoptotic pathways (Wolf et al., 2011, J. Biol. Chem.). This strategy is particularly promising for treating aggressive, glycolytic cancers that are resistant to conventional chemotherapy (Galluzzi et al., 2008, Biol. Chem.).

Other names

HKII-VDAC complexHexokinase 2-VDAC1 interactionMitochondrial HK2-VDAC interfaceHK2-VDAC1 PPI

Disruption of the protein-protein interaction between HK2 and VDAC1, leading to the detachment of HK2 from the outer mitochondrial membrane, which inhibits glycolysis and triggers mitochondria-mediated apoptosis (Galluzzi et al., 2008, Biol. Chem.; Goldin et al., 2008, Cancer Res.).