title: Extracellular Signal-Regulated Kinase/Nuclear Factor-Erythroid2-like2/Heme Oxygenase-1 Pathway-Mediated Mitophagy Alleviates Traumatic Brain Injury-Induced Intestinal Mucosa Damage and Epithelial Barrier Dysfunction.
abstract: Gastrointestinal dysfunction is one of several physiologic complications in patients with traumatic brain injury (TBI). TBI can result in increased intestinal permeability resulting from apoptosis of intestinal epithelial cells, which contain a large number of mitochondria for persisting barrier function. Autophagy of damaged mitochondria (mitophagy) controls the quality of the mitochondria and regulates cellular homeostasis. However, the exact mechanism of mitophagy that underlies the pathological changes induced by TBI is unknown. Here, we report that mitophagy decreases the intestinal epithelial cell damage and apoptosis that are activated in a rat model of controlled cortical impact (CCI). CCI-induced mitophagy is associated with an increase in 3-nitrotyrosine and 4-hydroxynonenal, indicating that oxidative stress may increase in response to mitochondrial disturbance. CCI also results in the expression of the tight junction proteins zonula occludens-1 (ZO-1) and occludin, which may regulate the in vivo intestinal hyperpermeability induced by CCI. Additionally, CCI-induced mitophagy was shown to be mediated by the oxidative stress-related extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid2-like2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway, which may serve to reduce the apoptosis induced by oxidative stress. These results suggest that CCI-induced mitophagy serves to diminish apoptosis-mediated intestinal epithelial cell damage and to improve intestinal permeability, via ERK/Nrf2/HO-1 signaling. These findings may be useful in the design of rational approaches for the prevention and treatment of symptoms associated with TBI.
authors.affiliation: 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Yinlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Bao
authors.affiliation: 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Xiupeng
authors.initials: X
authors.lastname: Xu
authors.affiliation: 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Honglu
authors.initials: H
authors.lastname: Chao
authors.affiliation: 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Chao
authors.initials: C
authors.lastname: Lin
authors.affiliation: 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: 2 Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 3 Department of Immunology, Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Yongping
authors.initials: Y
authors.lastname: You
authors.affiliation: 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: 1 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China .
authors.forename: Jing
authors.initials: J
authors.lastname: Ji
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D063306:Mitophagy / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C002744:3-nitrotyrosine; D014443:Tyrosine; D051547:Heme Oxygenase-1; D048049:Extracellular Signal-Regulated MAP Kinases; C027576:4-hydroxy-2-nonenal
keywords: TBI; intestinal dysfunction; intestinal mucosa damage; mitophagy; oxidative stress