Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death.

TitleVoltage-dependent anion channels are dispensable for mitochondrial-dependent cell death.
Publication TypeJournal Article
Year of Publication2007
AuthorsBaines, CP, Kaiser, RA, Sheiko, T, Craigen, WJ, Molkentin, JD
JournalNat Cell Biol
Volume9
Issue5
Pagination550-5
Date Published2007 May
ISSN1465-7392
KeywordsAnimals, Apoptosis, Calcium, Caspases, Cell Death, Cell Membrane Permeability, Cells, Cultured, Cyclophilins, Cytochromes c, Mice, Mice, Knockout, Mitochondria, Heart, Mitochondria, Liver, Mitochondrial ADP, ATP Translocases, Mitochondrial Membrane Transport Proteins, Mitochondrial Membranes, Mitochondrial Proteins, Mitochondrial Swelling, Oxidative Stress, Proto-Oncogene Proteins c-bcl-2, RNA Interference, RNA, Small Interfering, Time Factors, Transfection, Voltage-Dependent Anion Channel 1, Voltage-Dependent Anion Channel 2, Voltage-Dependent Anion Channels
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.

DOI10.1038/ncb1575
Alternate JournalNat. Cell Biol.
Citation Key10.1038/ncb1575
PubMed ID17417626
PubMed Central IDPMC2680246
Grant ListR01 HL081104-04 / HL / NHLBI NIH HHS / United States
P01 HL069779-06A10003 / HL / NHLBI NIH HHS / United States
P50 HL077101-050004 / HL / NHLBI NIH HHS / United States
P01 HL069779 / HL / NHLBI NIH HHS / United States
R01 HL062927 / HL / NHLBI NIH HHS / United States
R01 HL060562-11 / HL / NHLBI NIH HHS / United States
R01 HL062927-10A1 / HL / NHLBI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 HL081104 / HL / NHLBI NIH HHS / United States
R01 HL060562 / HL / NHLBI NIH HHS / United States
P50 HL077101 / HL / NHLBI NIH HHS / United States