Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death.
Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis and tissue homeostasis. In mammals, release of mitochondrial cytochrome c leads to the cytosolic assembly of the apoptosome-a caspase activation complex involving Apaf1 and caspase-9 that induces hallmarks of apoptosis. There are, however, mitochondrially regulated cell death pathways that are independent of Apaf1/caspase-9. We have previously cloned a molecule associated with programmed cell death called apoptosis-inducing factor (AIF). Like cytochrome c, AIF is localized to mitochondria and released in response to death stimuli. Here we show that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation. Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies-the very first wave of cell death indispensable for mouse morphogenesis. AIF-dependent cell death displays structural features of apoptosis, and can be genetically uncoupled from Apaf1 and caspase-9 expression. Our data provide genetic evidence for a caspase-independent pathway of programmed cell death that controls early morphogenesis.
Joza
N
N
Amgen Institute, 620 University Avenue, Toronto, Ontario, Canada M5G 2C1.
Susin
S A
SA
Daugas
E
E
Stanford
W L
WL
Cho
S K
SK
Li
C Y
CY
Sasaki
T
T
Elia
A J
AJ
Cheng
H Y
HY
Ravagnan
L
L
Ferri
K F
KF
Zamzami
N
N
Wakeham
A
A
Hakem
R
R
Yoshida
H
H
Kong
Y Y
YY
Mak
T W
TW
Zúñiga-Pflücker
J C
JC
Kroemer
G
G
Penninger
J M
JM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor; D053477:Apoptotic Protease-Activating Factor 1; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002678:Chimera; D004622:Embryo, Mammalian / Q000166:cytology; D005314:Embryonic and Fetal Development / Q000502:physiology; D005260:Female; D005420:Flavoproteins / Q000235:genetics / Q000502:physiology*; D018390:Gene Targeting; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D009024:Morphogenesis; D011506:Proteins / Q000502:physiology; D011995:Recombination, Genetic; D013234:Stem Cells
C506593:Apaf1 protein, mouse; D051033:Apoptosis Inducing Factor; D053477:Apoptotic Protease-Activating Factor 1; D005420:Flavoproteins; D008565:Membrane Proteins; C494830:AIFM1 protein, mouse; D011506:Proteins; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases