Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.
Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1-dependent cell death. N-methyl-N'-nitro-N-nitrosoguanidine, H2O2, and N-methyl-d-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1-dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.
Department of Neurology and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Seong-Woon
SW
Yu
Hongmin
H
Wang
Marc F
MF
Poitras
Carmen
C
Coombs
William J
WJ
Bowers
Howard J
HJ
Federoff
Guy G
GG
Poirier
Ted M
TM
Dawson
Valina L
VL
Dawson
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005420:Flavoproteins / Q000276:immunology / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018384:Oxidative Stress; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D000906:Antibodies; D051033:Apoptosis Inducing Factor; D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D005420:Flavoproteins; D008565:Membrane Proteins; C494830:AIFM1 protein, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016194:Receptors, N-Methyl-D-Aspartate; D009243:NAD; D008769:Methylnitronitrosoguanidine; D016202:N-Methylaspartate; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases