Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide.
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.
Zheng
Yanhua
Y
The Laboratory of Apoptosis and Cancer Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, PR China.
Shi
Yong
Y
Tian
Changhai
C
Jiang
Chunsun
C
Jin
Haijing
H
Chen
Jianjun
J
Almasan
Alex
A
Tang
Hong
H
Chen
Quan
Q
D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045304:Cytochromes c / Q000032:analysis*; D005434:Flow Cytometry; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000502:physiology*; D008930:Mitochondria, Liver / Q000502:physiology; D009101:Multiple Myeloma; D010087:Oxides / Q000494:pharmacology*; D010539:Permeability; D018272:Porins / Q000502:physiology*; D011510:Proteolipids / Q000378:metabolism; D014407:Tumor Cells, Cultured; D050994:Voltage-Dependent Anion Channels
D017304:Annexin A5; D001152:Arsenicals; D010087:Oxides; D018272:Porins; D011510:Proteolipids; D050994:Voltage-Dependent Anion Channels; C020485:proteoliposomes; D045304:Cytochromes c; D000077237:Arsenic Trioxide