Outer membrane VDAC1 controls permeability transition of the inner mitochondrial membrane in cellulo during stress-induced apoptosis.
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.
Tomasello
Flora
F
INSERM U916, Université Bordeaux 2, Institut Bergonié, 33076 Bordeaux, France.
Messina
Angela
A
Lartigue
Lydia
L
Schembri
Laura
L
Medina
Chantal
C
Reina
Simona
S
Thoraval
Didier
D
Crouzet
Marc
M
Ichas
François
F
De Pinto
Vito
V
De Giorgi
Francesca
F
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D019556:COS Cells; D002463:Cell Membrane Permeability / Q000502:physiology; D002522:Chlorocebus aethiops; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D018038:Sodium Selenite / Q000494:pharmacology; D013312:Stress, Physiological / Q000502:physiology*; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000081406:Peptidyl-Prolyl Isomerase F; C494762:VDAC1 protein, human; D016572:Cyclosporine; D050995:Voltage-Dependent Anion Channel 1; D021983:Cyclophilins; D018038:Sodium Selenite