title: Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation.
abstract: Loss of mitochondrial membrane integrity and the resulting release of apoptogenic factors may play a critical role in mediating hippocampal neurodegeneration after transient global ischemia. In the present study, the authors have cloned and characterized the rat cDNA encoding apoptosis-inducing factor (AIF), an intramitochondrial protein that promotes cell death in a caspase-independent manner upon release into nonmitochondrial compartments. In contrast to the expression patterns of a number of apoptosis-regulatory gene products during brain development, the expression of AIF protein increases gradually with brain maturation and peaks in adulthood. In a rat model of transient global ischemia, AIF was found to translocate from mitochondria to the nucleus in the hippocampal CA1 neurons after ischemia and to manifest a DNA-degrading activity that mimicked the purified AIF protein and was inhibitable by AIF immunodepletion. The temporal profile of AIF translocation after ischemia (24 to 72 hours) coincided with the induction of large-scale DNA fragmentation at the size of 50 kbp, a well-characterized hallmark of AIF-like activity but preceded the formation of internucleosomal DNA fragmentation (72 hours), a DNA degradation associated with the terminal stage of cell death. Further, the nuclear translocation of AIF after ischemia was not blocked by inhibiting caspase-3/-7 activities, but, as shown in neuronal cultures that were challenged with transient oxygen-glucose deprivation, it can be prevented by intracellular delivery of the mitochondria-associated antiapoptotic protein Bcl-xL. The results presented here strongly suggest that mitochondrial release of AIF may be an important factor, in addition to the previously reported cytochrome c and Smac, which could contribute to the selective vulnerability of CA1 neurons to transient global ischemic injury.
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Cao
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
authors.forename: Wei
authors.initials: W
authors.lastname: Pei
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Feng-Yan
authors.initials: FY
authors.lastname: Sun
authors.forename: Steven H
authors.initials: SH
authors.lastname: Graham
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051033:Apoptosis Inducing Factor; D001483:Base Sequence; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018076:DNA, Complementary; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051020:bcl-X Protein
chemical_list: C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; C494813:Bcl2l1 protein, rat; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D018076:DNA, Complementary; D005420:Flavoproteins; D008565:Membrane Proteins; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D005947:Glucose; D010100:Oxygen