Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death.
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.
Baines
Christopher P
CP
Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Kaiser
Robert A
RA
Sheiko
Tatiana
T
Craigen
William J
WJ
Molkentin
Jeffery D
JD
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism; D008933:Mitochondrial Swelling; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism; D050996:Voltage-Dependent Anion Channel 2 / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; C000631446:PPIF protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C494763:Vdac1 protein, mouse; C494766:Vdac2 protein, mouse; C480078:Vdac3 protein, mouse; D050996:Voltage-Dependent Anion Channel 2; D050994:Voltage-Dependent Anion Channels; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; D050995:Voltage-Dependent Anion Channel 1; D020169:Caspases; D021983:Cyclophilins; D002118:Calcium