vidac technology vdac hk2Both HK1 and HK2 attach to the mitochondria via interaction with the voltage-dependent anion channel 1 (VDAC1) on the cytosolic side of the outer mitochondrial membrane (OMM). The VDAC1 channel allows passage of many ions and metabolites, such as ATP, ADP, NADH, Ca2+ and many others, thus controlling the metabolic cross-talk between the mitochondria and the rest of the cell. VDAC1, too, is overexpressed in many cancer types and plays an important role in cancer proliferation1. While the association of HK1 to VDAC1 is strong and continuous, the binding of HK2 to VDAC1 is much weaker, oscillating between the cytoplasm and the mitochondrial-bound states2. This process is highly regulated in both normal and disease states and is controlled by the metabolic and energetic requirements of the cells.

HK2-VDAC1 binding confers great advantages to the cancer cell3. First, VDAC1-bound HK2 protects cells from apoptosis. In this way VDAC1 regulates the release of apoptotic or anti-apoptotic factors from the mitochondria, on the one hand, while interacting with factors such as Bax, Bak, and HK2 in the cytosol, on the other hand. Second, by binding to the VDAC1 channel, HK2 gains privileged access to ATP synthesized in the mitochondria by oxidative phosphorylation, which is the preferred source for its substrate utilization. Finally, the association between VDAC1 and HK2 results in reduced sensitivity to feedback inhibition by the product, G6P4.

  1. Shoshan-Barmatz V and Mizrachi D (2012), Front Oncol 2: 1
  2. John S et al (2011), PLoS one 6: e17674
  3. Krasnov GS et al (2013), Exp Opin Ther Targets 17: 10
  4. Wilson JE (2003), J Exp Biol 206: 2049