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.

p62/SQSTM1 at the interface of aging, autophagy, and disease

“…This is recognized as a signal to recruit the E3 ligase parkin from the cytosol to the mitochondria (Narendra et al 2010b). Here, parkin tags several mitochondrial outer membrane proteins with K63-and K27-linked poly-ubiquitin chains (Narendra et al 2010a;Geisler et al 2010a;Okatsu et al 2010). Once the mitochondrial proteins are tagged with ubiquitin, p62/SQSTM1 associates with them and drives the whole organelle into sequestosomes that are then cleared by autophagy (Narendra et al 2010a;Geisler et al 2010a).…”

NBR1 acts as an autophagy receptor for peroxisomes

“…Several groups have reported that p62 is involved in mitophagy (the autophagic degradation of mitochondria); however, it is not clear whether p62 is required for targeting of ubiquitylated mitochondria to autophagosomes or serves a different functional role (Ding et al, 2010;Geisler et al, 2010;Narendra et al, 2010;Okatsu et al, 2010). Recently, we showed that p62 is involved in selective degradation of peroxisomes when peroxisomes were labeled with ubiquitin .…”

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

“…1,36 In neuronal cells, SQSTM1 is required for ubiquitination-dependent clustering of damaged mitochondria caused by treatment with a mitochondrial uncoupler, carbonyl cyanide m-chlorophenylhydrazone. 6,18,37 Thus, we hypothesized that SESN2 may induce perinuclear clustering of mitochondria by mediating the aggregation of SQSTM1 via SESN2-SQSTM1 interaction and by linking SQSTM1 to ubiquitins on the surface of damaged mitochondria. As shown in Fig.…”

“…7,14,15 Activated PARK2 promotes ubiquitination of outer membrane proteins on the mitochondria, which in turn triggers translocation of the ubiquitin-binding receptor SQSTM1 or NBR1 (neighbor of Brca1 gene 1) to mitochondria, thus completing mitochondrial priming. 6,[16][17][18][19] Among the components of the autophagy machinery required for mitophagy, ULK1 and BNIP3L (BCL2/adenovirus E1B 19kDa interacting protein 3-like), are critical for clearance of mitochondria during erythroid cell maturation. 2,20,21 However, it remains unclear how these 2 steps are connected so that the mitophagy process can be completed under inflammatory conditions.…”