Journal
CELL RESEARCH
Volume 19, Issue 12, Pages 1363-1376Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2009.98
Keywords
apoptosis; mitochondria; VDAC; MPT; PTP; oxidative stress; selenite
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Funding
- l'INSERM
- la Region Aquitaine
- le Ministere de la Recherche
- l'Institut Bergonie
- la Ligue Contre le Cancer
- le Canceropole Grand Sud-Ouest
- et l'Association France Cancer
- FIRB RBRN07BMCT
- University of Catania
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Voltage-dependent anion channel (VDAC) 1 is the main channel of the mitochondrial outer membrane (MOM) and it has been proposed to be part of the permeability transition pore (PTP), a putative multiprotein complex candidate agent of the mitochondrial permeability transition (MPT). Working at the single live cell level, we found that overexpression of VDAC1 triggers MPT at the mitochondrial inner membrane (MIM). Conversely, silencing VDAC1 expression results in the inhibition of MPT caused by selenite-induced oxidative stress. This MOM-MIM crosstalk was modulated by Cyclosporin A and mitochondrial Cyclophilin D, but not by Bcl-2 and Bcl-XL, indicative of PTP operation. VDAC1-dependent MPT engages a positive feedback loop involving reactive oxygen species and p38-MAPK, and secondarily triggers a canonical apoptotic response including Bax activation, cytochrome c release and caspase 3 activation. Our data thus support a model of the PTP complex involving VDAC1 at the MOM, and indicate that VDAC1-dependent MPT is an upstream mechanism playing a causal role in oxidative stress-induced apoptosis.
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