Shuaipeng Ma1, Xuefei Zhang1, Liangjun Zheng1, Zeyang Li1, Xuyang Zhao2, Wenjia Lai3, Hongyan Shen4, Junniao Lv1, Guofeng Yang5, Qingsong Wang1, Jianguo Ji1. 1. 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China . 2. 2 Institute of System Biomedicine, School of Basic Medical Sciences, Peking University , Beijing, China . 3. 3 National Center for Nanoscience and Technology , Beijing, China . 4. 4 Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics , Chinese Academy of Sciences, Beijing, China . 5. 5 Department of Neurology, The Second Hospital of Hebei Medical University , Shijiazhuang, China .
Abstract
AIMS: 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. INNOVATION: 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. CONCLUSION: 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.
AIMS: 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. INNOVATION: 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. CONCLUSION: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: Jonathan P Gumucio; Austin H Qasawa; Patrick J Ferrara; Afshan N Malik; Katsuhiko Funai; Brian McDonagh; Christopher L Mendias Journal: FASEB J Date: 2019-04-02 Impact factor: 5.191
Authors: Marie-Therese Mackmull; Luise Nagel; Fabian Sesterhenn; Jan Muntel; Jan Grossbach; Patrick Stalder; Roland Bruderer; Lukas Reiter; Wilma D J van de Berg; Natalie de Souza; Andreas Beyer; Paola Picotti Journal: Nat Struct Mol Biol Date: 2022-10-12 Impact factor: 18.361