Outer membrane VDAC1 controls permeability transition of the inner mitochondrial membrane in cellulo during stress-induced apoptosis
Cell Res. 2009-08-11; 19(12): 1363-1376
DOI: 10.1038/cr.2009.98
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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-X(L), 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.