p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria.
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.
Okatsu
Kei
K
Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
Saisho
Keiko
K
Shimanuki
Midori
M
Nakada
Kazuto
K
Shitara
Hiroshi
H
Sou
Yu-Shin
YS
Kimura
Mayumi
M
Sato
Shigeto
S
Hattori
Nobutaka
N
Komatsu
Masaaki
M
Tanaka
Keiji
K
Matsuda
Noriyuki
N
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
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