A BAX/BAK and cyclophilin D-independent intrinsic apoptosis pathway.
Most intrinsic death signals converge into the activation of pro-apoptotic BCL-2 family members BAX and BAK at the mitochondria, resulting in the release of cytochrome c and apoptosome activation. Chronic endoplasmic reticulum (ER) stress leads to apoptosis through the upregulation of a subset of pro-apoptotic BH3-only proteins, activating BAX and BAK at the mitochondria. Here we provide evidence indicating that the full resistance of BAX and BAK double deficient (DKO) cells to ER stress is reverted by stimulation in combination with mild serum withdrawal. Cell death under these conditions was characterized by the appearance of classical apoptosis markers, caspase-9 activation, release of cytochrome c, and was inhibited by knocking down caspase-9, but insensitive to BCL-X(L) overexpression. Similarly, the resistance of BIM and PUMA double deficient cells to ER stress was reverted by mild serum withdrawal. Surprisingly, BAX/BAK-independent cell death did not require Cyclophilin D (CypD) expression, an important regulator of the mitochondrial permeability transition pore. Our results suggest the existence of an alternative intrinsic apoptosis pathway emerging from a cross talk between the ER and the mitochondria.
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.
Sebastián
S
Zamorano
Diego
D
Rojas-Rivera
Fernanda
F
Lisbona
Valentina
V
Parra
Felipe A
FA
Court
Rosario
R
Villegas
Emily H
EH
Cheng
Stanley J
SJ
Korsmeyer
Sergio
S
Lavandero
Claudio
C
Hetz
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001769:Blood; D053453:Caspase 9 / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D051379:Mice; D056811:Unfolded Protein Response; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000502:physiology*
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D053453:Caspase 9; D021983:Cyclophilins