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BNIP3 regulates mitophagy and apoptosis in delayed neuronal death in stroke
Author(s) -
Shi Ruoyang,
Kong Jiming
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.533.6
Subject(s) - neuroprotection , mitophagy , autophagy , apoptosis , regulator , microbiology and biotechnology , programmed cell death , western blot , biology , neurotoxicity , tunel assay , gene , neuroscience , medicine , genetics , toxicity
Physiological level of autophagy promotes neuronal survival, while apoptosis contributes to delayed neuronal death in ischemic stroke. In this study, we show that the proapoptotic BCL‐2 family member BNIP3 is an upstream regulator for both processes. Specifically, deletion of BNIP3 gene is neuroprotective by affecting mitophagy and apoptosis pathways. We performed IHC, western blot, Co‐ip, ELISA, and cell transfection to analyze the BNIP3's regulation on mitophagy and apoptosis in cortical neurons and ischemic brains. Both BNIP3 wild‐type and knock‐out mice were used. In primary neurons exposed to OGD/reperfusion, BNIP3 was highly expressed, with the time course and expression levels of apoptosis‐related proteins (i.e. active caspase‐3, cytochrome C, and BAX) and autophagy‐related proteins (i.e. LC3, Beclin‐1, and LAMP‐2) positively regulated. Promoting or inhibiting autophagy pharmacologically didn't affect the expression patterns of BNIP3, indicating it is an upstream regulator. We also measured the brain damage of neonatal stroke in transgenic mice. TTC staining showed the infarct volume of ischemic brains was significantly reduced in BNIP3 KO mice compared to WT mice upon 3–7 days recovery. Silence of BNIP3 gene in cortical neurons of KO mice activated a robust autophagic response and decreased apoptosis, coordinately contributing to the neuroprotection in the KO animals after stroke. Grant Funding Source : Canadian Institute of Health Research, Canadian Stroke Network, Manitoba Health Research Council, Manitoba Institute of Child Health