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

Federica Chiara, Diego Castellaro, Oriano Marin, Valeria Petronilli, William S. Brusilow, Magdalena Juhaszova, Steven J. Sollott, Michael Forte, Paolo Bernardi, Andrea Rasola

Research output: Contribution to journalArticle

183 Scopus citations

Abstract

Type II hexokinase is overexpressed in most neoplastic cell, and it mainly localizes on the outer mitochondrial membrane. Hexokinase II dissociation from mitochondria triggers apoptosis. The prevailing model postulates that hexokinase II 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 factor signalling. Here we show that a hexokinase II N-terminal peptide selectively detaches hexokinase II from mitochondria and activates apoptosis. These events are abrogated by inhibiting two established permeability transition pore modulators, the adenine nucleotide translocator or cyclophilin D, or in cyclophilin D knock-out cells. Conversely, insulin stimulation or genetic ablation of the voltage-dependent anion channel do not affect cell death induction by the hexokinase II peptide. Therefore, hexokinase II detachment from mitochondria transduces a permeability transition pore opening signal that results in cell death and does not require the voltage-dependent anion channel. These findings have profound implication for our understanding of the pathways of outer mitochondrial membrane permeabilization and their inactivation in tumors.

Original languageEnglish (US)
Article numbere1852
JournalPloS one
Volume3
Issue number3
DOIs
StatePublished - Mar 19 2008

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Chiara, F., Castellaro, D., Marin, O., Petronilli, V., Brusilow, W. S., Juhaszova, M., Sollott, S. J., Forte, M., Bernardi, P., & Rasola, A. (2008). Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels. PloS one, 3(3), [e1852]. https://doi.org/10.1371/journal.pone.0001852