Abstract
Mitochondria release proteins that propagate both caspase-dependent and caspase-independent cell death pathways. AIF (apoptosis-inducing factor) is an important caspase-independent death regulator in multiple neuronal injury pathways. Presently, there is considerable controversy as to whether AIF is neuroprotective or proapoptotic in neuronal injury, such as oxidative stress or excitotoxicity. To evaluate the role of AIF in BAX-dependent (DNA damage induced) and BAX-independent (excitotoxic) neuronal death, we used Harlequin (Hq) mice, which are hypomorphic for AIF. Neurons carrying double mutations for Hq/Apaf1-/- (apoptosis proteases-activating factor) are impaired in both caspase-dependent and AIF-mediated mitochondrial cell death pathways. These mutant cells exhibit extended neuroprotection against DNA damage, as well as glutamate-induced excitotoxicity. Specifically, AIF is involved in NMDA- and kainic acid- but not AMPA-induced excitotoxicity. In vivo excitotoxic studies using kainic acid-induced seizure showed that Hq mice had significantly less hippocampal damage than wild-type littermates. Our results demonstrate an important role for AIF in both BAX-dependent and BAX-independent mechanisms of neuronal injury.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology*
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Apoptosis Inducing Factor
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Apoptotic Protease-Activating Factor 1
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Benzodiazepines / pharmacology
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Benzothiadiazines / pharmacology
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Camptothecin / pharmacology
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Caspase Inhibitors
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Cells, Cultured / cytology
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Cerebellum / cytology
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Cerebral Cortex / cytology
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Convulsants / toxicity
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Dizocilpine Maleate / pharmacology
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Drug Resistance
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Flavoproteins / genetics
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Flavoproteins / physiology*
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Glutamic Acid / pharmacology
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Glycine / pharmacology
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Hippocampus / drug effects
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Hippocampus / metabolism
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Hippocampus / pathology
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Kainic Acid / pharmacology
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Kainic Acid / toxicity
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Male
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Mice
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Mice, Knockout
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Mice, Mutant Strains
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N-Methylaspartate / pharmacology
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Neurons / cytology*
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Neurons / drug effects
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Neurons / metabolism
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Neurotoxins / pharmacology
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Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Recombinant Fusion Proteins / physiology
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Seizures / chemically induced
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Seizures / metabolism
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Seizures / pathology
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
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bcl-2-Associated X Protein
Substances
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Apaf1 protein, mouse
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Apoptosis Inducing Factor
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Apoptotic Protease-Activating Factor 1
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Bax protein, mouse
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Benzothiadiazines
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Caspase Inhibitors
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Convulsants
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Flavoproteins
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Membrane Proteins
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Neurotoxins
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AIFM1 protein, mouse
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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bcl-2-Associated X Protein
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GYKI 52466
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Benzodiazepines
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Glutamic Acid
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N-Methylaspartate
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Dizocilpine Maleate
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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cyclothiazide
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Kainic Acid
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Glycine
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Camptothecin