title: Early Stage Functions of Mitochondrial Autophagy and Oxidative Stress in Acetaminophen-Induced Liver Injury.
abstract: Mitochondria go through frequent cycles of fusion and fission, a process required for mitochondrial quality control by eliminating ROS-damaged mitochondria through mitochondrial autophagy. Acetaminophen (APAP) overdose can cause liver injury in animals and human beings by inducing mitochondrial damage, which need to be further evaluated. The aim of the current study is to assess the changes between oxidative damage mitophagy in vivo and in vitro, which mimics APAP-induced liver injury (AILI) in humans. Liver damage was monitored by measuring the levels of biochemical indexes. Proteins associated with oxidative stress were inspected by western blot analysis. After given APAP to both Nrf2-/-and wild-type mice, Nrf2-/-mice were highly susceptible to APAP induced liver injury. Actually, rapamycin promoted the process of autophagy, reducing the formation of giant mitochondria and lipid droplets. Both tBHQ and NAC protected hepatic cells, promoting Nrf2 translocation into nucleus and increasing the expression of downstream enzymes and proteins. C57BL/6 mice with stabilized Nrf2 had increased hepatic up-regulation of Nrf2 and other antioxidant enzymes, and reduced the mitochondria dysfunction. Interestingly, APAP-induced mitochondrial changes of Drp1; however, the initiation of mitochondria fission was inhibited by MDIVI-1, causing much more serious hepatic impairment. In the early stage of AILI, Nrf2 played a protective role in antioxidant activity while mitophagy protected against oxidative stress damage by the scavenging function. Promoting that both Drp1 and Nrf2 could be a promising new approach to reduce AILI. J. Cell. Biochem. 118: 3130-3141, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Chu
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zuo
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Congyuan
authors.initials: C
authors.lastname: Xia
authors.affiliation: College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Qidi
authors.initials: Q
authors.lastname: Ai
authors.affiliation: College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Piao
authors.initials: P
authors.lastname: Luo
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Academy of Traditional Chinese Medicine, 100 Shizi Street, Hongshan Road, Nanjing, Jiangsu, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Naihong
authors.initials: N
authors.lastname: Chen
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000401:mortality* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D000082:Acetaminophen
keywords: ACETAMINOPHEN; Drp1; MITOPHAGY; Nrf2; OXIDATIVE INJURY