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p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria
Author(s) -
Okatsu Kei,
Saisho Keiko,
Shimanuki Midori,
Nakada Kazuto,
Shitara Hiroshi,
Sou Yushin,
Kimura Mayumi,
Sato Shigeto,
Hattori Nobutaka,
Komatsu Masaaki,
Tanaka Keiji,
Matsuda Noriyuki
Publication year - 2010
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2010.01426.x
Subject(s) - parkin , pink1 , biology , mitochondrion , ubiquitin , ubiquitin ligase , aggresome , microbiology and biotechnology , mitophagy , proteasome , genetics , parkinson's disease , autophagy , gene , apoptosis , disease , medicine , pathology
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.