title: Parkin-induced ubiquitination of Mff promotes its association with p62/SQSTM1 during mitochondrial depolarization.
abstract: The ubiquitin ligase Parkin and autophagic adapter protein p62 are known to function in a common pathway controlling mitochondrial autophagy (mitophagy). However, the evidence supporting that p62 is directly recruited by ubiquitinated proteins remains undetermined. Here, we demonstrate that mitochondrial fission factor (Mff) associates with Parkin and carbonyl cyanide m-chlorophenyl hydrazone treatment significantly increases the affinity of Parkin with Mff. After recruitment to depolarized mitochondria, Parkin mediates poly-ubiquitination of Mff at lysine 251. Replacement of lysine 251 by arginine (K251R) totally abrogates Parkin-stimulated ubiquitination of Mff. Subsequently, the ubiquitinated Mff promotes its association with p62. Mff knockout interferes with p62 translocation to damaged mitochondria. Only re-transfection of Mff WT, but not K251R mutant, rescues this phenotype. Furthermore, loss of Mff results in failure of Parkin translocation and final clearance of damaged mitochondria. Thus, our data reveal functional links among Mff, p62, and the selective autophagy of mitochondria, which are implicated in the pathogenesis of neurodegeneration diseases.
authors.affiliation: Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Chengdu 610041, China Department of Pediatrics, West China 2nd University Hospital, Sichuan University, Chengdu 610041, China Key Laboratory for Molecular Biology of Neural Development, 1068 Xueyuan Blvd., Shenzhen 518055, China Institute of Biomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.affiliation: Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Chengdu 610041, China Department of Pediatrics, West China 2nd University Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Siyue
authors.initials: S
authors.lastname: Qin
authors.affiliation: Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Chengdu 610041, China Department of Pediatrics, West China 2nd University Hospital, Sichuan University, Chengdu 610041, China Key Laboratory for Molecular Biology of Neural Development, 1068 Xueyuan Blvd., Shenzhen 518055, China Institute of Biomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China ca.jiang@siat.ac.cn.
authors.forename: Chang'an
authors.initials: C
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C533267:Mff protein, human; D024101:Mitochondrial Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Mff; Parkin; mitophagy; p62/SQSTM1; ubiquitination