Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels

Type II hexokinase (HKII) is overexpressed in the outer mitochondrial membrane of most neoplastic cells. Current work postulates that HKII release from its mitochondrial interactor, the voltage-dependent anion channel, prompts outer mitochondrial membrane permeabilization and the ensuing release of apoptogenic proteins, and that these events are inhibited by growth factors. Here we show that a HKII Nterminal peptide selectively detaches HKII from mitochondria transduces a permeability transition pore opening signal that results in cell death, does not require the voltage-dependent anion channel and is not affected by insulin stimulation. These findings have implications for our understanding of the pathways of outer mitochondrial membrane permeabilization and their inactivation in tumors.