Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Antibodies / immunology
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Apoptosis Inducing Factor
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Apoptosis*
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Caspase Inhibitors
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Caspases / metabolism
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Cell Nucleus / metabolism
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Cells, Cultured
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Cytochrome c Group / metabolism
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Flavoproteins / immunology
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Flavoproteins / metabolism*
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Hydrogen Peroxide / pharmacology
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Membrane Potentials
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Methylnitronitrosoguanidine / pharmacology
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Mice
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Mice, Knockout
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Mitochondria / metabolism
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Mitochondria / physiology
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N-Methylaspartate / metabolism
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N-Methylaspartate / pharmacology
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NAD / metabolism
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Neurons / cytology
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Neurons / physiology
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Oxidative Stress
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptors, N-Methyl-D-Aspartate / metabolism
Substances
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Antibodies
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Apoptosis Inducing Factor
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Caspase Inhibitors
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Cytochrome c Group
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Enzyme Inhibitors
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Flavoproteins
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Membrane Proteins
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AIFM1 protein, mouse
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Poly(ADP-ribose) Polymerase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Receptors, N-Methyl-D-Aspartate
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NAD
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Methylnitronitrosoguanidine
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N-Methylaspartate
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Hydrogen Peroxide
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Poly(ADP-ribose) Polymerases
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Caspases