title: p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria.
abstract: PINK1 and Parkin were first identified as the causal genes responsible for familial forms of early-onset Parkinson's disease (PD), a prevalent neurodegenerative disorder. PINK1 encodes a mitochondrial serine/threonine protein kinase, whereas Parkin encodes an ubiquitin-protein ligase. PINK1 and Parkin cooperate to maintain mitochondrial integrity; however, the detailed molecular mechanism of how Parkin-catalyzed ubiquitylation results in mitochondrial integrity remains an enigma. In this study, we show that Parkin-catalyzed K63-linked polyubiquitylation of depolarized mitochondria resulted in ubiquitylated mitochondria being transported along microtubules to cluster in the perinuclear region, which was interfered by pathogenic mutations of Parkin. In addition, p62/SQSTM1 (hereafter referred to as p62) was recruited to depolarized mitochondria after Parkin-directed ubiquitylation. Intriguingly, deletion of p62 in mouse embryonic fibroblasts resulted in a gross loss of mitochondrial perinuclear clustering but did not hinder mitochondrial degradation. Thus, p62 is required for ubiquitylation-dependent clustering of damaged mitochondria, which resembles p62-mediated 'aggresome' formation of misfolded/unfolded proteins after ubiquitylation.
authors.affiliation: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Okatsu
authors.forename: Keiko
authors.initials: K
authors.lastname: Saisho
authors.forename: Midori
authors.initials: M
authors.lastname: Shimanuki
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shitara
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Sou
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kimura
authors.forename: Shigeto
authors.initials: S
authors.lastname: Sato
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Matsuda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055162:Biocatalysis; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D017510:Protein Folding; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004272:DNA, Mitochondrial; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein