Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia.
Signaling cascades associated with apoptosis contribute to cell death after focal cerebral ischemia. Cytochrome c release from mitochondria and the subsequent activation of caspases 9 and 3 are critical steps. Recently, a novel mitochondrial protein, apoptosis-inducing factor (AIF), has been implicated in caspase-independent programmed cell death following its translocation to the nucleus. We, therefore, addressed the question whether AIF also plays a role in cell death after focal cerebral ischemia. We detected AIF relocation from mitochondria to nucleus in primary cultured rat neurons 4 and 8 hours after 4 hours of oxygen/glucose deprivation. In ischemic mouse brain, AIF was detected within the nucleus 1 hour after reperfusion after 45 minutes occlusion of the middle cerebral artery. AIF translocation preceded cell death, occurred before or at the time when cytochrome c was released from mitochondria, and was evident within cells showing apoptosis-related DNA fragmentation. From these findings, we infer that AIF may be involved in neuronal cell death after focal cerebral ischemia and that caspase-independent signaling pathways downstream of mitochondria may play a role in apoptotic-like cell death after experimental stroke.
Plesnila
Nikolaus
N
Laboratory of Experimental Neurosurgery, Institute for Surgical Research, University of Munich, Germany. plesnila@icf.med.uni-muenchen.de
Zhu
Changlian
C
Culmsee
Carsten
C
Gröger
Moritz
M
Moskowitz
Michael A
MA
Blomgren
Klas
K
D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D015153:Blotting, Western; D002452:Cell Count; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003470:Culture Media; D004195:Disease Models, Animal; D005420:Flavoproteins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; D003470:Culture Media; D005420:Flavoproteins; D008565:Membrane Proteins; C494830:AIFM1 protein, mouse; D005947:Glucose; D010100:Oxygen