Hexokinase 2-Voltage-dependent anion channel complex (HK2-VDAC)

Hexokinase 2 (HK2) is a rate-limiting enzyme in glycolysis that is highly upregulated in many cancers to facilitate the Warburg effect. A critical feature of its function in malignant cells is its physical association with the Voltage-Dependent Anion Channel (VDAC) on the outer mitochondrial membrane (Pedersen, 2008). This mitochondrially bound HK2 (mtHK2) gains preferential access to ATP exported from the mitochondria, which accelerates glucose phosphorylation and provides a metabolic advantage for rapid proliferation (Galluzzi et al., 2008). Beyond metabolism, the HK2-VDAC complex acts as a molecular switch that suppresses apoptosis by preventing the recruitment of pro-apoptotic proteins like BAX and the subsequent release of cytochrome c (Azoulay-Zohar et al., 2004). Therapeutic strategies targeting this interface, such as the use of 3-bromopyruvate or HK2-displacing peptides, aim to decouple the enzyme from the mitochondria to trigger cell death and inhibit glycolytic flux (Ko et al., 2001; Chiara et al., 2008). Consequently, the HK2-VDAC interface represents a dual-action target for metabolic and pro-apoptotic cancer therapy.

Other names

Mitochondrially bound hexokinase IIHKII-VDAC interfaceMitochondrial HK2HK2-VDAC1 complexmtHK2

Dissociation of hexokinase 2 from the voltage-dependent anion channel (VDAC) to inhibit glycolytic flux and induce mitochondrial-mediated apoptosis.