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

Abstract

The precise molecular mechanism underlying arsenic trioxide (As(2)O(3))-induced apoptosis is a subject of extensive study. Here, we show that clinically relevant doses of As(2)O(3) can induce typical apoptosis in IM-9, a multiple myeloma cell line, in a Bcl-2 inhibitable manner. We confirmed that As(2)O(3) 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(2)O(3) responsible for eliciting cyto c release in apoptosis. First, pretreatment of the isolated mitochondria with an anti-VDAC antibody specifically prevented As(2)O(3)-induced cyto c release. Second, in proteoliposome experiments, VDAC by itself was sufficient to mediate As(2)O(3)-induced cyto c release, which could be specifically inhibited by Bcl-X(L). Third, As(2)O(3) induced mitochondria membrane potential (DeltaPsim) reduction and cyto c release only in the VDAC-expressing, but not in the VDAC-deficient yeast strain. Finally, we found that As(2)O(3) 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.

• Authors: Yanhua Zheng, Yong Shi, Changhai Tian, Chunsun Jiang, Haijing Jin, Jianjun Chen, Alex Almasan, Hong Tang, Quan Chen
• Journal: Oncogene (Oncogene) Vol. 23 Issue 6 Pg. 1239-47 (Feb 12 2004) ISSN: 0950-9232 [Print] England
• PMID: 14647451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Annexin A5
• Arsenicals
• Oxides
• Porins
• Proteolipids
• Voltage-Dependent Anion Channels
• proteoliposomes
• Cytochromes c
• Arsenic Trioxide

Topics

• Animals
• Annexin A5 (analysis)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Cytochromes c (analysis)
• Flow Cytometry
• Humans
• Intracellular Membranes (physiology)
• Ion Channel Gating (drug effects, physiology)
• Membrane Potentials (physiology)
• Mice
• Mice, Inbred BALB C
• Mitochondria (physiology)
• Mitochondria, Liver (physiology)
• Multiple Myeloma
• Oxides (pharmacology)
• Permeability
• Porins (physiology)
• Proteolipids (metabolism)
• Tumor Cells, Cultured
• Voltage-Dependent Anion Channels