The voltage-dependent anion channel-1 modulates apoptotic cell death

H. Zaid, S. Abu-Hamad, A. Israelson, I. Nathan, V. Shoshan-Barmatz

Research output: Contribution to journalArticlepeer-review

243 Scopus citations

Abstract

The role of the voltage-dependent anion channel (VDAC) in cell death was investigated using the expression of native and mutated murine VDAC1 in U-937 cells and VDAC inhibitors. Glutamate 72 in VDAC1, shown previously to bind dicyclohexylcarbodiimide (DCCD), which inhibits hexokinase isoform I (HK-I) binding to mitochondria, was mutated to glutamine. Binding of HK-I to mitochondria expressing E72Q-mVDAC1, as compared to native VDAC1, was decreased by ∼70% and rendered insensitive to DCCD. HK-I and ruthenium red (RuR) reduced the VDAC1 conductance but not that of E72Q-mVDAC1. Overexpression of native or E72Q-mVDAC1 in U-937 cells induced apoptotic cell death (80%). RuR or overexpression of HK-I prevented this apoptosis in cells expressing native but not E72Q-mVDAC1. Thus, a single amino-acid mutation in VDAC prevented HK-I- or RuR-mediated protection against apoptosis, suggesting the direct VDAC regulation of the mitochondria-mediated apoptotic pathway and that the protective effects of RuR and HK-I rely on their binding to VDAC.

Original languageEnglish
Pages (from-to)751-760
Number of pages10
JournalCell Death and Differentiation
Volume12
Issue number7
DOIs
StatePublished - 1 Jul 2005

Keywords

  • Apoptosis
  • Hexokinase
  • Mitochondria
  • Ruthenium red
  • VDAC

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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