Hexokinase 2 – interaction with Voltage-Dependent Anion Channel (HK2-VDAC)

Hexokinase 2 (HK2) is the rate-limiting enzyme that catalyzes the first step of glycolysis, and its interaction with the Voltage-Dependent Anion Channel (VDAC), specifically VDAC1, on the outer mitochondrial membrane is a hallmark of the Warburg effect in cancer cells (NIH, 2013; ResearchGate, 2013). This protein-protein interaction provides HK2 with preferential access to mitochondrial-generated ATP, facilitating rapid glucose phosphorylation and metabolic flux (NIH, 2024; Biomedres.us, 2024). Beyond its metabolic role, the HK2-VDAC complex acts as a potent anti-apoptotic switch by preventing the release of cytochrome c and inhibiting the formation of the mitochondrial permeability transition pore (MPTP) (NIH, 2013; NIH, 2025). Because HK2 is selectively overexpressed in many aggressive tumors compared to normal adult tissues, disrupting this interaction is a promising strategy for cancer therapy (ResearchGate, 2013; ResearchGate, 2024). Small molecules such as lonidamine and 3-bromopyruvate have been shown to dissociate HK2 from VDAC, thereby inducing apoptosis and sensitizing resistant tumors to chemotherapy (Biomedres.us, 2024; NIH, 2024). Targeting this complex offers a dual approach by simultaneously impairing tumor energy metabolism and activating cell death pathways (NIH, 2013; NIH, 2025).

Other names

HK2-VDAC1 complexMitochondrial Hexokinase 2 interactionHKII-VDAC interactionHexokinase 2-VDAC1 protein-protein interaction

Dissociation of the Hexokinase 2-VDAC complex, which inhibits glycolytic flux and triggers mitochondrial-mediated apoptosis by facilitating the release of pro-apoptotic factors like cytochrome c (NIH, 2013; Biomedres.us, 2024).