title: An acetyl-L-carnitine switch on mitochondrial dysfunction and rescue in the metabolomics study on aluminum oxide nanoparticles.
abstract: BACKGROUND
  Due to the wide application of engineered aluminum oxide nanoparticles and increased aluminum containing particulate matter suspending in air, exposure of human to nano-scale aluminum oxide nanoparticles (Al2O3 NPs) is becoming inevitable.
  
  
  METHODS
  In the present study, RNA microarray coupled with metabolomics analysis were used to uncover mechanisms underlying cellular responses to Al2O3 NPs and imply the potential rescue.
  
  
  RESULTS
  We found that Al2O3 NPs significantly triggered down-regulation of mitochondria-related genes located in complex I, IV and V, which were involved in oxidative phosphorylation and neural degeneration pathways, in human bronchial epithelial (HBE) cells. Subsequent cell- and animal- based assays confirmed that Al2O3 NPs caused mitochondria-dependent apoptosis and oxidative stress either in vitro or in vivo, which were consistent with the trends of gene regulation. To rescue the Al2O3 NPs induced mitochondria dysfunction, disruption of small molecular metabolites of HBE were profiled using metabolomics analysis, which facilitates identification of potential antagonizer or supplement against nanoparticle-involved damages. Supplementation of an antioxidant, acetyl-L-carnitine, completely or partially restored the Al2O3 NPs modulated gene expression levels in mitochondrial complex I, IV and V. It further reduced apoptosis and oxidative damages in both Al2O3 NPs treated HBE cells and animal lung tissues.
  
  
  CONCLUSIONS
  Thus, our results demonstrate the potential mechanism of respiratory system damages induced by Al2O3 NPs. Meanwhile, based on the metabolomics profiling, application of acetyl-L-carnitine is suggested to ameliorate mitochondria dysfunction associated with Al2O3 NPs.
authors.affiliation: Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Dingjiaqiao 87, Nanjing, 210009, China. 101011116@seu.edu.cn.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Dingjiaqiao 87, Nanjing, 210009, China. zhangchengcheng2015@hotmail.com.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Dingjiaqiao 87, Nanjing, 210009, China. xinzhang1202@hotmail.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Dingjiaqiao 87, Nanjing, 210009, China. shizhiwang2009@seu.edu.cn.
authors.forename: Shizhi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Dingjiaqiao 87, Nanjing, 210009, China. mqtmengqingtao@hotmail.com.
authors.forename: Qingtao
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Dingjiaqiao 87, Nanjing, 210009, China. shenshenwu2015@hotmail.com.
authors.forename: Shenshen
authors.initials: S
authors.lastname: Wu
authors.affiliation: Center for Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, 211198, China. yhb@cpu.edu.cn.
authors.forename: Hongbao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. yankaixia@njmu.edu.cn.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Dingjiaqiao 87, Nanjing, 210009, China. 101011816@seu.edu.cn.|State Key Laboratory of Bioelectronics, Southeast University, Nanjing, 210096, China. 101011816@seu.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D000108:Acetylcarnitine / Q000378:metabolism / Q000494:pharmacology*; D000537:Aluminum Oxide / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D055432:Metabolomics / Q000379:methods; D053768:Metal Nanoparticles; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D036103:Nanotechnology / Q000379:methods; D009410:Nerve Degeneration; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000187:drug effects; D013997:Time Factors
chemical_list: D000975:Antioxidants; C021983:complex V (mitochondrial oxidative phosphorylation system); D000108:Acetylcarnitine; D003576:Electron Transport Complex IV; D025261:Mitochondrial Proton-Translocating ATPases; D042967:Electron Transport Complex I; D000537:Aluminum Oxide