title: BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke.
abstract: BACKGROUND
  A basal level of mitophagy is essential in mitochondrial quality control in physiological conditions, while excessive mitophagy contributes to cell death in a number of diseases including ischemic stroke. Signals regulating this process remain unknown. BNIP3, a pro-apoptotic BH3-only protein, has been implicated as a regulator of mitophagy.
  
  
  OBJECTIVE
  Both in vivo and in vitro models of stroke, as well as BNIP3 wild-type and knock out mice were used in this study.
  
  
  RESULTS
  We show that BNIP3 and its homologue BNIP3L (NIX) are highly expressed in a "delayed" manner and contribute to delayed neuronal loss following stroke. Deficiency in BNIP3 significantly decreases both neuronal mitophagy and apoptosis but increases nonselective autophagy following ischemic/hypoxic insults. The mitochondria-localized BNIP3 interacts with the autophagosome-localized LC3, suggesting that BNIP3, similar to NIX, functions as a LC3-binding receptor on mitochondria. Although NIX expression is upregulated when BNIP3 is silenced, up-regulation of NIX cannot functionally compensate for the loss of BNIP3 in activating excessive mitophagy.
  
  
  CONCLUSIONS
  NIX primarily regulates basal level of mitophagy in physiological conditions, whereas BNIP3 exclusively activates excessive mitophagy leading to cell death.
authors.affiliation: Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Ruo-Yang
authors.initials: RY
authors.lastname: Shi
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Zhu
authors.forename: Victor
authors.initials: V
authors.lastname: Li
authors.forename: Spencer B
authors.initials: SB
authors.lastname: Gibson
authors.forename: Xing-Shun
authors.initials: XS
authors.lastname: Xu
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Kong
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020520:Brain Infarction / Q000209:etiology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics*; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D020521:Stroke / Q000150:complications; D013997:Time Factors
chemical_list: C508686:BNip3 protein, mouse; C480860:Map1lc3b protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D005947:Glucose
keywords: BNIP3; LC3; Mitophagy; NIX; Neonatal stroke