Letter abstract
Nature Cell Biology 9, 550 - 555 (2007)
Published online: 8 April 2007 | doi:10.1038/ncb1575
Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death
Christopher P. Baines1, Robert A. Kaiser1, Tatiana Sheiko2, William J. Craigen2 & Jeffery D. Molkentin1
Mitochondria are critically involved in necrotic cell death induced by Ca2+ 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 matrix1, 2, 3. 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 Ca2+- and oxidative stress-induced MPT that was indistinguishable from wild-type mitochondria. Similarly, Ca2+- 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.
- Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
- Departments of Molecular and Human Genetics, and Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Correspondence to: Jeffery D. Molkentin1 e-mail: jeff.molkentin@cchmc.org
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