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

The HK2–VDAC1 protein-protein interface is a biologically critical contact site located on the cytosolic face of the mitochondrial outer membrane, where hexokinase 2 (HK2) physically associates with voltage-dependent anion channel 1 (VDAC1)[1][2][4][5]. HK2 binds via its N-terminal mitochondrial targeting domain, anchoring itself to VDAC1 and allowing efficient access to ATP produced in mitochondria, thereby facilitating glycolysis and cell metabolism. In cancer cells, this interaction is upregulated and serves a dual role, promoting metabolic reprogramming and actively inhibiting apoptosis by blocking cytochrome c release[4][5]. Disruption of this interface, for example by phosphorylation of VDAC1 or inhibition/detachment of HK2, reactivates apoptosis and is a promising strategy for cancer therapeutics. The HK2–VDAC1 interface is also involved in inflammation (NLRP3 inflammasome regulation)[8] and may play roles in other diseases involving cell death. Experimental drugs and biological modulators are being developed to target this interface for cancer treatment, but systemic effects and metabolic toxicity remain key therapeutic challenges[5][4][6].

Other names

HKII–VDAC1 interactionHexokinase 2–mitochondrial VDAC1 binding siteHK2–VDAC complexHexokinase-mitochondrial channel interface

Disruption of interface: Promotes apoptosis by detaching HK2 from VDAC1 Inhibition of HK2 activity: Reduces glycolysis and ATP production, sensitizes cells to apoptosis Modulation of VDAC phosphorylation: Alters affinity of HK2 binding, controls cell fate Activation/inhibition of PKC, Akt, GSK3β pathways: Regulates VDAC1 phosphorylation and HK2 binding