BNIP3 upregulation and EndoG translocation in delayed neuronal death in stroke and in hypoxia.
OBJECTIVE
Delayed neuronal death is a hallmark feature of stroke and the primary target of neuroprotective strategies. Caspase-independent apoptosis pathways are suggested as a mechanism for the delayed neuronal injury. Here we test the hypothesis that one of the caspase-independent apoptosis pathways is activated by BNIP3 and mediated by EndoG.


METHODS
We performed immunohistochemistry, Western blotting, cell transfection, subcellular fractionation, and RNA interfering to analyze the expression and localization of BNIP3 and EndoG in degenerating neurons in models of stroke and hypoxia.


RESULTS
BNIP3 was upregulated in brain neurons in a rat model of stroke and in cultured primary neurons exposed to hypoxia. The expressed BNIP3 was localized to mitochondria. Both forced expression of BNIP3 by plasmid transfection and induced expression of BNIP3 by hypoxia in neurons resulted in mitochondrial release and nuclear translocation of EndoG and neuronal cell death. Knockdown of BNIP3 by RNAi inhibited EndoG translocation and protected against hypoxia-induced neuronal death.


CONCLUSIONS
BNIP3 plays a role in delayed neuronal death in hypoxia and stroke and EndoG is a mediator of the BNIP3-activated neuronal death pathway. The results suggest that BNIP3 may be a new target for neuronal rescue strategies.
Zhang
Zhengfeng
Z
Department of Human Anatomy and Cell Science, University of Manitoba, Faculty of Medicine, Winnipeg, Manitoba, Canada.
Yang
Xuefen
X
Zhang
Surong
S
Ma
Xiuli
X
Kong
Jiming
J
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D002534:Hypoxia, Brain / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000503:physiopathology*; D014178:Translocation, Genetic / Q000502:physiology; D015854:Up-Regulation
C505650:BNIP3 protein, rat; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins