Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide

Yanhua Zheng, Yong Shi, Changhai Tian, Chunsun Jiang, Haijing Jin, Jianjun Chen, Alex Almasan, Hong Tang, Quan Chen

Research output: Contribution to journalArticle

149 Scopus citations

Abstract

The precise molecular mechanism underlying arsenic trioxide (As 2O3)-induced apoptosis is a subject of extensive study. Here, we show that clinically relevant doses of As2O3 can induce typical apoptosis in IM-9, a multiple myeloma cell line, in a Bcl-2 inhibitable manner. We confirmed that As2O3 directly induced cytochrome c (cyto c) release from isolated mouse liver mitochondria via the mitochondrial permeability transition pore, and we further identified the voltage-dependent anion channel (VDAC) as a biological target of As 2O3 responsible for eliciting cyto c release in apoptosis. First, pretreatment of the isolated mitochondria with an anti-VDAC antibody specifically prevented As2O3-induced cyto c release. Second, in proteoliposome experiments, VDAC by itself was sufficient to mediate As2O3-induced cyto c release, which could be specifically inhibited by Bcl-XL. Third, As2O3 induced mitochondria membrane potential (ΔΨm) reduction and cyto c release only in the VDAC-expressing, but not in the VDAC-deficient yeast strain. Finally, we found that As2O3 induced the increased expression and homodimerization of VDAC in IM-9 cells, but not in Bcl-2 overexpressing cells, suggesting that VDAC homodimerization could potentially determine its gating capacity to cyto c, and Bcl-2 blockage of VDAC homodimerization represents a novel mechanism for its inhibition of apoptosis.

Original languageEnglish (US)
Pages (from-to)1239-1247
Number of pages9
JournalOncogene
Volume23
Issue number6
DOIs
StatePublished - Feb 12 2004

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Keywords

  • Apoptosis
  • Arsenic trioxide
  • Bcl-2 proteins
  • Cytochrome c
  • VDAC

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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