Abstract
Mitochondria are critically involved in necrotic cell death induced by Ca(2+) overload, hypoxia and oxidative damage. The mitochondrial permeability transition (MPT) pore - a protein complex that spans both the outer and inner mitochondrial membranes - is considered the mediator of this event and has been hypothesized to minimally consist of the voltage-dependent anion channel (Vdac) in the outer membrane, the adenine-nucleotide translocase (Ant) in the inner membrane and cyclophilin-D in the matrix. Here, we report the effects of deletion of the three mammalian Vdac genes on mitochondrial-dependent cell death. Mitochondria from Vdac1-, Vdac3-, and Vdac1-Vdac3-null mice exhibited a Ca(2+)- and oxidative stress-induced MPT that was indistinguishable from wild-type mitochondria. Similarly, Ca(2+)- and oxidative-stress-induced MPT and cell death was unaltered, or even exacerbated, in fibroblasts lacking Vdac1, Vdac2, Vdac3, Vdac1-Vdac3 and Vdac1-Vdac2-Vdac3. Wild-type and Vdac-deficient mitochondria and cells also exhibited equivalent cytochrome c release, caspase cleavage and cell death in response to the pro-death Bcl-2 family members Bax and Bid. These results indicate that Vdacs are dispensable for both MPT and Bcl-2 family member-driven cell death.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Calcium / metabolism
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Caspases / metabolism
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Cell Death
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Cell Membrane Permeability*
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Cells, Cultured
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Cyclophilins / metabolism
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Cytochromes c / metabolism
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Mice
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Mice, Knockout
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Mitochondria, Heart / metabolism*
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Mitochondria, Liver / metabolism*
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Mitochondrial ADP, ATP Translocases / metabolism
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Mitochondrial Membrane Transport Proteins / metabolism*
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Mitochondrial Membranes / metabolism*
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Mitochondrial Permeability Transition Pore
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Mitochondrial Proteins / metabolism
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Mitochondrial Swelling
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Oxidative Stress
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Peptidyl-Prolyl Isomerase F
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Proto-Oncogene Proteins c-bcl-2
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RNA Interference
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Time Factors
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Transfection
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Voltage-Dependent Anion Channel 1 / metabolism
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Voltage-Dependent Anion Channel 2 / metabolism
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Voltage-Dependent Anion Channels / deficiency
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Voltage-Dependent Anion Channels / genetics
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Voltage-Dependent Anion Channels / metabolism*
Substances
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Peptidyl-Prolyl Isomerase F
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Permeability Transition Pore
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Mitochondrial Proteins
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PPIF protein, mouse
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Vdac1 protein, mouse
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Vdac2 protein, mouse
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Vdac3 protein, mouse
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Voltage-Dependent Anion Channel 2
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Voltage-Dependent Anion Channels
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Cytochromes c
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Mitochondrial ADP, ATP Translocases
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Voltage-Dependent Anion Channel 1
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Caspases
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Cyclophilins
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Calcium