title: Peroxiredoxin 6 Is a Crucial Factor in the Initial Step of Mitochondrial Clearance and Is Upstream of the PINK1-Parkin Pathway.
abstract: OBJECTIVE
  PTEN-putative kinase 1 (PINK1)-Parkin-mediated mitophagy is crucial for the clearance of damaged mitochondria. However, the mechanisms underlying PINK1-Parkin-mediated mitophagy are not fully understood. The goal of this study is to identify new regulators and to elucidate the regulatory mechanisms of mitophagy.
  
  
  RESULTS
  Quantitative mitochondrial proteomic analysis revealed that 63 proteins showed increased levels and 36 proteins showed decreased levels in cells subjected to carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment. Peroxiredoxin 6 (PRDX6 or Prx6), a unique member of the ubiquitous PRDX family, was recruited to depolarized mitochondria. Reactive oxygen species (ROS) generated by CCCP promoted PRDX6 accumulation and PINK1 stabilization in damaged mitochondria and induced mitophagy. In addition, depletion of PRDX6 resulted in the stabilization of PINK1, accumulation of autophagic marker, p62, translocation of Parkin to mitochondria, and lipidation of microtubule-associated protein 1 light chain 3. Furthermore, these events were blocked upon supplementation with antioxidant N-acetyl-l-cysteine or depletion of PINK1.
  
  
  METHODS
  This is the first study to demonstrate that PRDX6 is the only member of the PRDX family that relocates to damaged mitochondria, where it plays a crucial role in the initial stage of mitophagy by controlling ROS homeostasis.
  
  
  CONCLUSIONS
  ROS induce the recruitment of PRDX6 to mitochondria, where PRDX6 controls ROS homeostasis in the initial step of PINK1-Parkin-mediated mitophagy. Our study provides new insight into the initial regulatory mechanisms of mitophagy and reveals the protective role of PRDX6 in the clearance of damaged mitochondria.
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Shuaipeng
authors.initials: S
authors.lastname: Ma
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Xuefei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Liangjun
authors.initials: L
authors.lastname: Zheng
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Zeyang
authors.initials: Z
authors.lastname: Li
authors.affiliation: 2 Institute of System Biomedicine, School of Basic Medical Sciences, Peking University , Beijing, China .
authors.forename: Xuyang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: 3 National Center for Nanoscience and Technology , Beijing, China .
authors.forename: Wenjia
authors.initials: W
authors.lastname: Lai
authors.affiliation: 4 Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics , Chinese Academy of Sciences, Beijing, China .
authors.forename: Hongyan
authors.initials: H
authors.lastname: Shen
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Junniao
authors.initials: J
authors.lastname: Lv
authors.affiliation: 5 Department of Neurology, The Second Hospital of Hebei Medical University , Shijiazhuang, China .
authors.forename: Guofeng
authors.initials: G
authors.lastname: Yang
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
mesh_terms: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects; D008954:Models, Biological; D054465:Peroxiredoxin VI / Q000378:metabolism*; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D020543:Proteome; D040901:Proteomics / Q000379:methods; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D054465:Peroxiredoxin VI; D011494:Protein Kinases; D020543:Proteome; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein