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Genes Cells. 2010 Aug;15(8):887-900. doi: 10.1111/j.1365-2443.2010.01426.x. Epub 2010 Jul 2.

p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria.

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  • 1Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.

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.

PMID:
20604804
[PubMed - indexed for MEDLINE]
PMCID:
PMC2970908
Free PMC Article
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