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

doi:10.1038/sj.onc.1207205

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 journal › Article › peer-review

173 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-X_L. 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 language	English
Pages (from-to)	1239-1247
Number of pages	9
Journal	Oncogene
Volume	23
Issue number	6
DOIs	https://doi.org/10.1038/sj.onc.1207205
State	Published - Feb 12 2004

Bibliographical note

Funding Information:
We are grateful to Professor Y Tsujimoto (Osaka University, Japan) for providing the Bcl-XL expression vector and VDAC antibodies, Dr M Forte (Vollum Institute, Oregon Health Sciences University, Portland, USA) for wild-type and VDAC-deficient yeast strains. We wish to thank Mrs J Wang and Mr XD Liao for their technical assistance in flow cytometry. We would like to thank our colleagues for helpful discussions. This work was supported by grants of ‘One hundred Elite Scholars Project’, ‘Knowledge Innovation Key Project’ of Chinese Academy of Sciences, and the National Proprietary Research Program (973 program project, No. 2002CB513100 and 2002CB513001) awarded to QC and HT, National Outstanding Young Investigator Fellowship of NSFC to HT (30025010), QC and National Institutes of Health (CA81504 and CA82858) to AA.

Keywords

Apoptosis
Arsenic trioxide
Bcl-2 proteins
Cytochrome c
VDAC

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "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 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.",

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

note = "Funding Information: We are grateful to Professor Y Tsujimoto (Osaka University, Japan) for providing the Bcl-XL expression vector and VDAC antibodies, Dr M Forte (Vollum Institute, Oregon Health Sciences University, Portland, USA) for wild-type and VDAC-deficient yeast strains. We wish to thank Mrs J Wang and Mr XD Liao for their technical assistance in flow cytometry. We would like to thank our colleagues for helpful discussions. This work was supported by grants of {\textquoteleft}One hundred Elite Scholars Project{\textquoteright}, {\textquoteleft}Knowledge Innovation Key Project{\textquoteright} of Chinese Academy of Sciences, and the National Proprietary Research Program (973 program project, No. 2002CB513100 and 2002CB513001) awarded to QC and HT, National Outstanding Young Investigator Fellowship of NSFC to HT (30025010), QC and National Institutes of Health (CA81504 and CA82858) to AA.",

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AU - Zheng, Yanhua

AU - Shi, Yong

AU - Tian, Changhai

AU - Jiang, Chunsun

AU - Jin, Haijing

AU - Chen, Jianjun

AU - Almasan, Alex

AU - Tang, Hong

AU - Chen, Quan

N1 - Funding Information: We are grateful to Professor Y Tsujimoto (Osaka University, Japan) for providing the Bcl-XL expression vector and VDAC antibodies, Dr M Forte (Vollum Institute, Oregon Health Sciences University, Portland, USA) for wild-type and VDAC-deficient yeast strains. We wish to thank Mrs J Wang and Mr XD Liao for their technical assistance in flow cytometry. We would like to thank our colleagues for helpful discussions. This work was supported by grants of ‘One hundred Elite Scholars Project’, ‘Knowledge Innovation Key Project’ of Chinese Academy of Sciences, and the National Proprietary Research Program (973 program project, No. 2002CB513100 and 2002CB513001) awarded to QC and HT, National Outstanding Young Investigator Fellowship of NSFC to HT (30025010), QC and National Institutes of Health (CA81504 and CA82858) to AA.

PY - 2004/2/12

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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