The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index; none of the 37 sources its claims cite is checked for support yet.
p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria
Open accessAbstract
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.
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Written from the paper’s full text.
TL;DR
Parkin-catalyzed K63-linked ubiquitylation of depolarized mitochondria drives their microtubule-dependent perinuclear clustering, and p62/SQSTM1 is required for this clustering but not for mitochondrial degradation in MEFs. The study links Parkin, p62, and aggresome-like mitochondrial quarantine, while leaving the role of p62 in mitophagy unresolved.
Key findings
- Parkin rapidly moved to CCCP-depolarized mitochondria and ubiquitylated them by t = 1 h; mitochondria later concentrated in the perinuclear region at t > 4 h in Parkin-expressing HeLa cells, and this clustering was Parkin dependent.
- Linkage-specific antibodies showed that Parkin-localized mitochondria were stained by K63-linked ubiquitin antibodies Apu3 and HWA4C4, but not by K48-linked Apu2; signals disappeared with E3-inactivated Parkin mutations T415N and G430D.
- Microtubule inhibitors nocodazole (10 μg/mL) and colchicine (50 μg/mL) dissipated perinuclear mitochondrial clusters, whereas latrunculin A/B had no effect.
- p62 was recruited to depolarized mitochondria after Parkin-directed ubiquitylation; p62 deletion in MEFs caused gross loss of perinuclear clustering but did not hinder degradation. mtDNA 12s rRNA after CCCP fell to 62 ± 4% in wild-type MEFs, 95 ± 13% in Atg7−/− MEFs, and 43 ± 2% in p62−/− MEFs.
- p62 PB1 mutant K7A/D69A failed to restore clustering in p62−/− MEFs, whereas W340A restored clustering but delayed mitochondrial degradation.
Methods
- HeLa cells expressing HA-Parkin or pathogenic Parkin mutants were treated with 10 μM CCCP; MEFs (wild-type, p62−/−, Atg7−/−) expressing HA- or GFP-Parkin were treated with 30 μM CCCP and analyzed by immunocytochemistry.
- Mitochondrial morphology was scored in more than 100 cells per condition across at least three experiments, with Welch’s t-test or Student’s t-test where reported; linkage-specific anti-ubiquitin antibodies were validated by immunoblotting against K48- or K63-linked polyubiquitin chains.
- Additional assays included COX electron microscopy, real-time quantitative PCR for mitochondrial 12s ribosomal RNA normalized to GAPDH, and inhibitor treatments with bafilomycin A1 or E64d/pepstatin A/NH4Cl.
Limitations
- The paper states that its results “do not rule out completely the involvement of p62 in Parkin-mediated mitophagy” and that a role for p62 in degradation is substitutable in MEFs, possibly due to functional redundancy with proteins such as NBR1, Alfy, and BAG3.
- The authors note their p62 result conflicts with Geisler et al. (2010), who reported p62 is required for Parkin-dependent mitophagy; they attribute the discrepancy to methodological differences (p62 knockout MEFs versus p62 siRNA in HeLa cells) and state further analysis is needed.
- Evident from the text: the study relies on cultured HeLa cells and MEFs with exogenous Parkin and CCCP-induced depolarization, not in vivo neurons; MEFs required higher CCCP concentrations and longer incubation than HeLa cells, and the p62−/− phenotype was interpreted with possible redundant factors.
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30 Own result · 23 Not checked yet · 17 Own interpretation · 6 Own method · 3 No basis given
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In the paper
“The K161N, K211N and T240R mutations, which severely compromised the mitochondrial localization of Parkin (Geisler et al. 2010; Matsuda et al. 2010; Narendra et al. 2010), inhibited the mitochondrial clustering.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Various pathogenic mutations of Parkin impede mitochondrial clustering
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In the paper
“Under steady-state conditions in HeLa cells, endogenous p62 was mainly localized throughout the cytosol irrespective of the presence or absence of Parkin, whereas p62 was rapidly recruited to the mitochondria only in Parkin-expressing cells after CCCP treatment for 1 h (Fig. 4A), as also reported by Springer et al. recently (Geisler et al. 2010).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > p62/SQSTM1 is not essential for mitochondrial degradation
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In the paper
“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.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Abstract
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In the paper
“In addition, p62/SQSTM1 (hereafter referred to as p62) was recruited to depolarized mitochondria after Parkin-directed ubiquitylation.”
- Also stated in: § p62/SQSTM1 is not essential for mitochondrial degradation · plain
“whereas p62 was rapidly recruited to the mitochondria only in Parkin-expressing cells after CCCP treatment for 1 h (Fig. 4A)”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Abstract
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- Also stated in: § p62/SQSTM1 is not essential for mitochondrial degradation · plain
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In the paper
“which was interfered by pathogenic mutations of Parkin.”
- Also stated in: § Various pathogenic mutations of Parkin impede mitochondrial clustering · plain
“Various pathogenic mutations of Parkin impede mitochondrial clustering”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Various pathogenic mutations of Parkin impede mitochondrial clustering · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Intriguingly, deletion of p62 in mouse embryonic fibroblasts resulted in a gross loss of mitochondrial perinuclear clustering but did not hinder mitochondrial degradation.”
- Also stated in: § p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria · plain
“we noticed that the perinuclear clustering of depolarized mitochondria was almost completely inhibited in p62 deficient MEFs (Fig. 6A–C).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Abstract
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- Also stated in: § p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After treatment with nocodazole (10 μg/mL) or colchicine (50 μg/mL), the perinuclear mitochondria clusters dissipated (Fig. 2A).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Mitochondrial clustering is microtubule dependent
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In the paper
“Interestingly, mitochondria later concentrated to the perinuclear region at t > 4 h (Fig. 1A,B) and finally degraded as reported (Narendra et al. 2008) (not shown).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Parkin-catalyzed K63-linked polyubiquitylation promotes mitochondrial clustering
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“but did not hinder mitochondrial degradation.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Abstract
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In the paper
“These results suggest that Parkin ubiquitylates the damaged mitochondria mainly via K63-linked polyubiquitylation and are consistent, in part, with the recent report by Geisler et al. (2010).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Parkin-catalyzed K63-linked polyubiquitylation promotes mitochondrial clustering
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In the paper
“In the R275W and C352G mutations, Parkin associated with depolarized mitochondria, but mitochondrial ubiquitylation and juxtanuclear clustering were severely inhibited (Fig. 3C and not shown).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Various pathogenic mutations of Parkin impede mitochondrial clustering
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In the paper
“This perinuclear transport and clustering of mitochondria are Parkin dependent, because this phenomenon was only observed in Parkin-expressing HeLa cells that lack an endogenous Parkin gene (Denison et al. 2003) (Fig. 1A, panel 3).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Parkin-catalyzed K63-linked polyubiquitylation promotes mitochondrial clustering
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In mitochondria fragmented with the mitochondrial uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), Parkin quickly moved to depolarized mitochondria and ubiquitylated them (t = 1 h).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Parkin-catalyzed K63-linked polyubiquitylation promotes mitochondrial clustering
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In wild-type MEFs, p62 was again selectively recruited to the mitochondria after CCCP treatment at t = 4 h, although the transport efficiency was lower than that of HeLa cells (data not shown), and depolarized mitochondria were later clustered in the perinuclear region similar to HeLa cells at t > 12 h (Fig. 5A).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > p62/SQSTM1 is not essential for mitochondrial degradation
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In the paper
“Mitochondrial localization of p62 was only observed in Parkin-expressing cells and disappeared when Parkin mutants deficient in substrate recognition or E3 activity (R275W, C352G, T415N and G430D; Fig. 3A) were introduced (Fig. 4), suggesting that ubiquitylation-catalyzed Parkin is required for the recruitment of p62 onto depolarized mitochondria.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > p62/SQSTM1 is not essential for mitochondrial degradation
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In the paper
“Electron microscopic analysis showed that juxtanuclear-clustered mitochondria aggregated in grape-like clusters and not fused to each other to make single large mitochondrion (Fig. 5C).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > p62/SQSTM1 is not essential for mitochondrial degradation
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In the paper
“PINK1 then recruits Parkin from the cytoplasm to depolarized mitochondria that then undergo Parkin-catalyzed ubiquitylation, meaning that PINK1 and Parkin cooperate to ubiquitylate mitochondria with low membrane potentials (Narendra et al. 2008, 2010; Geisler et al. 2010; Matsuda et al. 2010; Vives-Bauza et al. 2010).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Introduction
What the sources say
- Not checked yetcites Narendra et al. 2008, 2010
- Not checked yetcites Geisler et al. 2010
- Not checked yetcites Matsuda et al. 2010
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In the paper
“PINK1 then recruits Parkin from the cytoplasm to depolarized mitochondria that then undergo Parkin-catalyzed ubiquitylation, meaning that PINK1 and Parkin cooperate to ubiquitylate mitochondria with low membrane potentials (Narendra et al. 2008, 2010; Geisler et al. 2010; Matsuda et al. 2010; Vives-Bauza et al. 2010).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Introduction
What the sources say
- Not checked yetcites Narendra et al. 2008, 2010
- Not checked yetcites Geisler et al. 2010
- Not checked yetcites Matsuda et al. 2010
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In the paper
“Parkin has the potential to catalyze several types of ubiquitylation: multiple monoubiquitylation, Lys-48-linked polyubiquitylation and Lys-63-linked polyubiquitylation (Lim 2007; Matsuda & Tanaka 2010).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Parkin-catalyzed K63-linked polyubiquitylation promotes mitochondrial clustering
What the sources say
- Not checked yetcites Lim 2007
- Not checked yetcites Matsuda & Tanaka 2010
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In the paper
“Staining with single antibodies alone indicated that the merged data described earlier were not derived from channel crosstalk (Fig. S1 in Supporting Information).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > p62/SQSTM1 is not essential for mitochondrial degradation
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In the paper
“p62 can interact with both ubiquitin and the autophagic machinery LC-3 (Bjorkoy et al. 2005; Komatsu et al. 2007; Pankiv et al. 2007; Ichimura et al. 2008; Noda et al. 2008; Shvets et al. 2008) and thus p62 is a plausible factor that links Parkin-catalyzed ubiquitylation with mitochondrial degradation via autophagy.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > p62/SQSTM1 is not essential for mitochondrial degradation
What the sources say
- Not checked yetcites Bjorkoy et al. 2005
- Not checked yetcites Komatsu et al. 2007
- Not checked yetcites Pankiv et al. 2007
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In the paper
“bafilomycin A1 (an inhibitor of vacuolar-type H+-ATPase that prevents autophagosome-lysosome fusion and/or intralysosomal degradation)”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > p62/SQSTM1 is not essential for mitochondrial degradation
What the sources say
- Not checked yetcites Mizushima et al. 2010
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In the paper
“Immunoblotting against K48- and K63-linked polyubiquitin chains, whose linkage was directly confirmed by MALDI-TOF mass spectrometry (data not shown), showed the high specificity of the antibodies (Fig. 1C).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Parkin-catalyzed K63-linked polyubiquitylation promotes mitochondrial clustering
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In the paper
“However, overproduction of mutant ubiquitin can change the ubiquitylation linkage, and thus careful interpretation of observed results is required (Pickart & Raasi 2005; Saeki et al. 2009).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Parkin-catalyzed K63-linked polyubiquitylation promotes mitochondrial clustering
What the sources say
- Not checked yetcites Pickart & Raasi 2005
- Not checked yetcites Saeki et al. 2009
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In the paper
“Moreover, PINK1 functions upstream of Parkin, because forced overexpression of Parkin rescues loss-of-function phenotypes of PINK1 but not vice versa (Clark et al. 2006; Park et al. 2006; Yang et al. 2006).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Introduction
What the sources say
- Not checked yetcites Clark et al. 2006
- Not checked yetcites Park et al. 2006
- Not checked yetcites Yang et al. 2006
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“To check the specificity of linkage-specific anti-ubiquitin antibodies, Lys 48- or Lys 63-linked polyubiquitin chain (Enzo Life Sciences) was used as a positive control and subjected to immunoblotting.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Experimental procedures > Immunocytochemistry
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In the paper
“mitochondria are delivered to areas of the axon where metabolic demand is high, such as synapses, active growth cones and branches (Hollenbeck & Saxton 2005).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Discussion > Function of depolarized mitochondria juxtanuclear clustering
What the sources say
- Not checked yetcites Hollenbeck & Saxton 2005
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In the paper
“To prevent carry-over contamination, 0.5 unit of Uracil DNA Glycosylase (Invitrogen) was added during PCR”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Experimental procedures > Measurement of mitochondrial DNA contents
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In the paper
“(note that complete disruption of p62 cannot cause this type of titration and thus cannot confer the dominant effect).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Discussion > Function of p62 in the degradation of depolarized mitochondria
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- Rests on an assumption: Complete disruption of p62 cannot cause this type of titration and thus cannot confer the dominant effect.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and thus mitochondrial clustering might be involved in this process.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Discussion > Function of depolarized mitochondria juxtanuclear clustering
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In the paper
“with mitochondria-dedicated selective autophagy (termed mitophagy) considered to be essential for this clearance pathway (Narendra et al. 2008; Twig et al. 2008).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Introduction
What the sources say
- Not checked yetcites Narendra et al. 2008
- Not checked yetcites Twig et al. 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“samples were prepared in triplicate for each condition.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Experimental procedures > Measurement of mitochondrial DNA contents
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In the paper
“These results suggest that oligomerization of p62 but not interaction with LC3 is essential for the mitochondrial clustering triggered by Parkin.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria
What the sources say
- Not checked yetcites Lamark et al. 2003
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The K7A/D69A double mutation in the PB1 domain abolishes p62 oligomerization.
In the paper
“The defect in p62−/− MEFs, however, is concealed by other functionally redundant protein(s) (see Discussion).”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria
What the sources say
- Not checked yetcites Kirkin et al. 2009
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“methodological differences (i.e. we used p62 knockout MEFs whereas they used p62 siRNA in HeLa cells) may account for the conflicting observations”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Discussion > Function of p62 in the degradation of depolarized mitochondria
What the sources say
- Not checked yetcites Geisler et al. (2010)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The most plausible explanation for this result is that the p62 W340A mutant competes for certain common factor(s) with functionally redundant protein(s), and thus has a dominant effect”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Discussion > Function of p62 in the degradation of depolarized mitochondria
hedgeddirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The p62 W340A mutant cannot interact with LC3.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The similarity between aggresome and mitochondrial clustering, although superficial at the moment, suggests that the two ubiquitin-mediated cytoprotective events have something in common.”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Discussion > Function of depolarized mitochondria juxtanuclear clustering
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This series of events is reminiscent of aggresome formation”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Discussion > Function of depolarized mitochondria juxtanuclear clustering
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Endogenous Parkin is undetectable in mouse embryonic fibroblasts.
“Because endogenous Parkin is undetectable in MEFs, HA- or GFP-Parkin was introduced into control (p62+/+) and p62 KO (p62−/−) MEFs (Komatsu et al. 2007) by retro-viral transfection (Kitamura et al. 2003).”
The paper relies on this without support.
MEFs are less sensitive than HeLa cells to CCCP, requiring higher concentrations and longer incubation to observe the phenotype.
“Because MEFs are less sensitive than HeLa cells to CCCP, higher concentrations of CCCP (30 μm) and longer incubation are required to observe the phenotype.”
The paper relies on this without support.
The p62 W340A mutant cannot interact with LC3.
“the p62 W340A mutant, which cannot interact with LC3 (Fig. 7B)”
The paper relies on this without support.
Complete disruption of p62 cannot cause this type of titration and thus cannot confer the dominant effect.
“(note that complete disruption of p62 cannot cause this type of titration and thus cannot confer the dominant effect).”
The paper relies on this without support.
The K7A/D69A double mutation in the PB1 domain abolishes p62 oligomerization.
“we introduced a K7A/D69A double mutation in the PB1 domain”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“This results in the preferential degradation of mitochondrial outer membrane proteins by the proteasome, while inner membrane proteins and mitochondrial DNA 558 remain intact.”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [558]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“During mitochondrial degradation in cultured cells, depolarized mitochondria cluster with p6224. Depolarized mitochondria are ubiquitylated by Parkin, recognized by p62, transported via microtubules to aggregates, and degraded by autophagy.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [24]
Experimental — accuracy not yet measuredIn the citing paper
“During mitochondrial degradation in cultured cells, depolarized mitochondria cluster with p6224.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [24]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Discussion > Function of p62 in the degradation of depolarized mitochondria
“They showed that knockdown of p62 in HeLa cells dramatically inhibited the final clearance of damaged mitochondria”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Discussion > Function of p62 in the degradation of depolarized mitochondria
“cells with uncleared mitochondria decreased from 85% to 20% with p62 siRNA treatment.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Various pathogenic mutations of Parkin impede mitochondrial clustering
“HA-Parkin mutants harboring one of eight pathogenic mutations (R42P, K161N, T240R, R275W, C352G, T415N and G430D; Fig. 3A)”
§ p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria > Results > Various pathogenic mutations of Parkin impede mitochondrial clustering
“The K161N, K211N and T240R mutations, which severely compromised the mitochondrial localization of Parkin (Geisler et al. 2010; Matsuda et al. 2010; Narendra et al. 2010), inhibited the mitochondrial clustering.”
Citations
Cites
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., & Shimizu, N. (1998) · Nature · doi:10.1038/33416 · Cited by 5,227 · cited 1×
“One familial form of the PD gene causing autosomal recessive juvenile Parkinsonism (AR-JP) is Parkin (also known as PARK2), which encodes an E3 ubiquitin ligase, a substrate recognition member of the ubiquitylation pathway (Kitada et al. 1998; Shimura et al. 2000).”
BackgroundSelf-citationPankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J.-A., Outzen, H., Øvervatn, A., Bjørkøy, G., & Johansen, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702824200 · Cited by 4,578
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497 · cited 2×
“Moreover, treatment with bafilomycin A1 (an inhibitor of vacuolar-type H-ATPase that prevents autophagosome-lysosome fusion and ⁄ or intralysosomal degradation) or a cocktail of lysosomal inhibitors (E64d, pepstatin A and ammonium chloride) (Mizushima et al. 2010) inhibited the mitochondrial degradation of p62 ⁄ ) MEF…”
BackgroundParkin is recruited selectively to impaired mitochondria and promotes their autophagy
Narendra, D., Tanaka, A., Suen, D.-F., & Youle, R. J. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200809125 · Cited by 4,026 · cited 5×
“…endogenous and exogenous stresses, such as unnecessary generation of reactive oxygen species (ROS) and mtDNA mutations, is critical, with mitochondria-dedicated selective autophagy (termed mitophagy) considered to be essential for this clearance pathway (Narendra et al. 2008; Twig et al. 2008).”
BackgroundInfluentialHereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1
Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., et al. (2004) · Science · doi:10.1126/science.1096284 · Cited by 3,481 · cited 2×
“The other early-onset PD gene encodes a mitochondria-targeted serine-threonine kinase termed PTEN induced putative kinase 1 (PINK1) (Valente et al. 2004).”
BackgroundBjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Øvervatn, A., Stenmark, H., & Johansen, T. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200507002 · Cited by 3,276
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., et al. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601963 · Cited by 3,082 · cited 2×
“…endogenous and exogenous stresses, such as unnecessary generation of reactive oxygen species (ROS) and mtDNA mutations, is critical, with mitochondria-dedicated selective autophagy (termed mitophagy) considered to be essential for this clearance pathway (Narendra et al. 2008; Twig et al. 2008).”
BackgroundPINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
Narendra, D. P., Jin, S. M., Tanaka, A., Suen, D.-F., Gautier, C. A., Shen, J., Cookson, M. R., & Youle, R. J. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000298 · Cited by 2,944 · cited 5×
“…by likely inhibiting an as-yet-unknown processing protease that catalyzes conversion of the mature PINK1 (approximately 60 kDa) to an intermediate short form (approximately 50 kDa), which is further exclusively degraded by the proteasome pathway (Matsuda et al. 2010; Narendra et al. 2010).”
BackgroundInfluentialPINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Geisler, S., Holmström, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J., & Springer, W. (2010) · Nature Cell Biology · doi:10.1038/ncb2012 · Cited by 2,835 · cited 10×
“PINK1 then recruits Parkin from the cytoplasm to depolarized mitochondria that then undergo Parkin-catalyzed ubiquitylation, meaning that PINK1 and Parkin cooperate to ubiquitylate mitochondria with low membrane potentials (Narendra et al. 2008, 2010; Geisler et al. 2010; Matsuda et al. 2010; Vives-Bauza et al. 2010).”
BackgroundMethodInfluentialImpairment of starvation-induced and constitutive autophagy in Atg7 -deficient mice
Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200412022 · Cited by 2,331 · cited 1×
“When Atg7 (an essential gene for autophagy) KO MEFs (Komatsu et al. 2005) were used as a positive control, the clearance of depolarized mitochondria was considerably impeded after CCCP treatment for 24 h [Fig.”
MethodSelf-citation
Cited by
Sorted by citations
Items 201–300 of 399
Regulation of mitophagy in ischemic brain injury
Yuan, Y., Zhang, X., Zheng, Y., & Chen, Z. (2015) · Neuroscience Bulletin · doi:10.1007/s12264-015-1544-6 · Cited by 58
Ubiquitination-mediated autophagy against invading bacteria
Fujita, N., & Yoshimori, T. (2011) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2011.03.003 · Cited by 54
Hattori, N., Saiki, S., & Imai, Y. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.05.012 · Cited by 54
Self-citationMitochondrial quality control in neurodegenerative diseases
Dupuis, L. (2013) · Biochimie · doi:10.1016/j.biochi.2013.07.033 · Cited by 55
de Castro, I. P., Costa, A. C. O., Celardo, I., Tufi, R., Dinsdale, D. D., Loh, S. H. Y., & Martins, L. M. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.394 · Cited by 57
Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration
Muto, V., Flex, E., Kupchinsky, Z. A., Primiano, G., Galehdari, H., Dehghani, M., Cecchetti, S., Carpentieri, G., Rizza, T., Mazaheri, N., et al. (2018) · Neurology · doi:10.1212/wnl.0000000000005869 · Cited by 52
Miyai, T., Vasanth, S., Melangath, G., Deshpande, N., Kumar, V., Benischke, A., Chen, Y., Price, M. O., Price, F. W., & Jurkunas, U. V. (2019) · American Journal Of Pathology · doi:10.1016/j.ajpath.2019.06.012 · Cited by 53
PINK1: A Bridge between Mitochondria and Parkinson’s Disease
Gonçalves, F. B., & Morais, V. A. (2021) · Life · doi:10.3390/life11050371 · Cited by 52
“The p62 or sequestome-1 (SQSTM1) role in this pathway is still controversial, while a number of studies demonstrate that it is recruited to depolarized mitochondria [71,72], others show that it is not essential for mitophagy to occur [73].”
BackgroundLiu, C., Li, H., Duan, W., Duan, Y., Yu, Q., Zhang, T., Sun, Y., Li, Y., Liu, Y., & Xu, S. (2023) · Advanced Science · doi:10.1002/advs.202203869 · Cited by 52
The receptor proteins: pivotal roles in selective autophagy
Xu, Z., Yang, L., Xu, S., Zhang, Z., & Cao, Y. (2015) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmv055 · Cited by 57
“[80] indicates that the deletion of p62 results in a gross loss of mitochondrial perinuclear clustering, but does not hinder mitochondrial degradation.”
BackgroundTsakiri, E. N., Gumeni, S., Vougas, K. N., Pendin, D., Papassideri, I. S., Daga, A., Gorgoulis, V. G., Juhász, G., Scorrano, L., & Trougakos, I. P. (2019) · Autophagy · doi:10.1080/15548627.2019.1596477 · Cited by 54
“siological tubular mitochondrial network collapses into mitochondrial aggregates and/or large perinuclear clusters (Figure 2(g)); this phenotype represents a well-known feature of ongoing cell death [28,29] and/or mitophagy due to mitochondria depolarization [30].”
BackgroundChen, Y., Li, Q., Li, Q., Xing, S., Liu, Y., Liu, Y., Chen, Y., Liu, W., Feng, F., & Sun, H. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02038 · Cited by 56
Pathophysiological Role of Autophagy: Lesson from Autophagy-Deficient Mouse Models
Ichimura, Y., & Komatsu, M. (2011) · EXPERIMENTAL ANIMALS · doi:10.1538/expanim.60.329 · Cited by 50
Self-citationThe Physiological Role of Mitophagy: New Insights into Phosphorylation Events
Hirota, Y., Kang, D., & Kanki, T. (2012) · International Journal of Cell Biology · doi:10.1155/2012/354914 · Cited by 50
“Although it is accepted that p62 associates with mitochondrial proteins ubiquitinated by Parkin and mediates the aggregation of mitochondria, there have been conflicting reports showing that p62 is not indispensable for mitophagy [56, 57].”
BackgroundPUMA dependent mitophagy by Abrus agglutinin contributes to apoptosis through ceramide generation
Panda, P. K., Naik, P. P., Meher, B. R., Das, D. N., Mukhopadhyay, S., Praharaj, P. P., Maiti, T. K., & Bhutia, S. K. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.12.002 · Cited by 50
“evidence indicating that p62 is dispensable in the case of the Parkinmediated mitophagy [34,39] and that AGG induced mitophagy can function in a p62 dependent as well as independent manner.”
BackgroundCastets, P., Frank, S., Sinnreich, M., & Rüegg, M. A. (2016) · Journal of Neuromuscular Diseases · doi:10.3233/jnd-160153 · Cited by 49
“In mouse muscle, gene expression was increased after as little as 12 hrs of starvation, but remained unchanged from fed to basal conditions when constitutive autophagy was induced [76].”
Backgroundde Pablo, R., Saide, A., Polishhuck, E. V., Nusco, E., Fraldi, A., & Ballabio, A. (2012) · Human Molecular Genetics · doi:10.1093/hmg/ddr610 · Cited by 50
Activation of the E3 ubiquitin ligase Parkin
Caulfield, T. R., Fiesel, F. C., & Springer, W. (2015) · Biochemical Society Transactions · doi:10.1042/bst20140321 · Cited by 49
Molecular Functions of Glycoconjugates in Autophagy
Fahie, K., & Zachara, N. E. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.06.011 · Cited by 53
“This mitochondrial localization is associated with membrane depolarization, a known pro-autophagic stimulus [8, 15, 16].”
BackgroundInfluentialEdenharter, O., Schneuwly, S., & Navarro, J. A. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00038 · Cited by 44
Hsieh, C., & Yang, W. (2019) · Nature Communications · doi:10.1038/s41467-019-08924-5 · Cited by 44
“A tandem PH domain of PLCδ fused to EGFP was also utilized to monitor intracellular PtdIns(4,5)P2 levels during mitophagy25.”
BackgroundMethodInfluentialAutophagy-Related Deubiquitinating Enzymes Involved in Health and Disease
Magraoui, F. E., Reidick, C., Meyer, H. E., & Platta, H. W. (2015) · Cells · doi:10.3390/cells4040596 · Cited by 48
“proteins attracts the autophagy-receptor p62 [120,121], which simultaneously binds to ubiquitin and LC3 [127].”
BackgroundUbiquitin-like proteins and autophagy at a glance
Shpilka, T., Mizushima, N., & Elazar, Z. (2012) · Journal of Cell Science · doi:10.1242/jcs.093757 · Cited by 53
“Although p62 has been reported to function as an adaptor protein for Parkin-mediated mitophagy, this idea remains controversial (Narendra et al., 2010; Okatsu et al., 2010).”
BackgroundGao, B., Yu, W., Lv, P., Liang, X., Sun, S., & Zhang, Y. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165997 · Cited by 48
Metabolic control of mitophagy
Zimmermann, A., Madeo, F., Diwan, A., Sadoshima, J., Sedej, S., Kroemer, G., & Abdellatif, M. (2023) · European Journal of Clinical Investigation · doi:10.1111/eci.14138 · Cited by 49
“28,29”
Bell, C., English, L., Boulais, J., Chemali, M., Caron-Lizotte, O., Desjardins, M., & Thibault, P. (2013) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m112.025775 · Cited by 46
“adaptor protein that binds to Lys-63 polyubiquitin chains of ubiquitylated substrates and mediates the interaction with LC3 to facilitate the autophagosomal degradation of the damaged mitochondria (56).”
BackgroundMacrophages as Emerging Key Players in Mitochondrial Transfers
Pang, Y., Zhang, C., & Gao, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.747377 · Cited by 47
“Unwanted mitochondria then are marked by parkinmediated ubiquitination in the outer mitochondrial membrane and recognized by autophagosomes (Pankiv et al., 2007; Matsuda et al., 2010; Okatsu et al., 2010).”
BackgroundAutophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates
Yang, Z., Yoshii, S. R., Sakai, Y., Zhang, J., Chino, H., Knorr, R. L., & Mizushima, N. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00272-5 · Cited by 47
“EV1A,B) (Wong and Holzbaur, 2014), which appears to be consistent with the role of p62 in promoting mitochondrial clustering (Narendra et al, 2010; Okatsu et al, 2010).”
Phase separation of p62: roles and regulations in autophagy
Huang, X. S., Zhang, J., Yao, J., Mi, N., & Yang, A. (2025) · Trends in Cell Biology · doi:10.1016/j.tcb.2025.01.010 · Cited by 46
Koyano, F., & Matsuda, N. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.02.009 · Cited by 46
Self-citationJosé, C., Melser, S., Bénard, G., & Rossignol, R. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4357 · Cited by 51
“It is not clear whether p62 and Parkin are essential for mitochondrial degradation, as there are conflicting reports on the role of both proteins (90, 198).”
Sequestosome 1/p62: across diseases
Geetha, T., Viswaprakash, N., Sycheva, M., & Babu, J. R. (2012) · Biomarkers · doi:10.3109/1354750x.2011.653986 · Cited by 48
“Ubiquitinated mitochondria shuttle through microtubules to form aggregates in the perinuclear region and are degraded by autophagy (Geisler et al. 2010; Okatsu et al. 2010).”
BackgroundInfluentialNBR1 is dispensable for PARK2-mediated mitophagy regardless of the presence or absence of SQSTM1
Shi, J., Fung, G., Deng, H., Zhang, J.-Q., Fiesel, F. C., Springer, W., Li, X. X., & Luo, H. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.278 · Cited by 49
“These data indicate that SQSTM1 is not an essential modulator in the removal of damaged mitochondria, in agreement with previous reports.(23,34) The role of NBR1 in mitophagy J Shi et al 2”
BackgroundResultChew, K. C. M., Matsuda, N., Saisho, K., Lim, G. G. Y., Chai, C., Tan, H.-M., Tanaka, K., & Lim, K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019720 · Cited by 44
“Notably, several recent reports from our laboratories and others have uncovered parkin’s function in the surveillance pathway for damaged mitochondria [24,25,26, 27,28,29,30].”
BackgroundSelf-citationGiallongo, C., Tibullo, D., Puglisi, F., Barbato, A., Vicario, N., Cambria, D., Parrinello, N. L., Romano, A., Conticello, C., Forte, S., et al. (2020) · Cancers · doi:10.3390/cancers12081999 · Cited by 43
“Moreover, investigating the expression of p62/SQSTM1, which regulates mitochondrial clustering during mitophagy [32,33], we observed that both BTZ and TAK-242 alone increased p62/SQSTM1 expression, whilst their combination significantly downregulated the protein level compared to BTZ alone (p < 0.”
BackgroundTsai, W.-T., Lo, Y.-C., Wu, M.-S., Li, C., Kuo, Y.-P., Lai, Y.-H., Tsai, Y., Chen, K.-C., Chuang, T., Yao, C.-H., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.686683 · Cited by 42
“7 cells were transfected with pEGFP-N2 (Clontech) or SQSTM1/pCMV6-ACGFP (Origene RG203214) by Lipofectamine 2000 (Invitrogen) and selected by Geneticin (Invitrogen).”
BackgroundInfluentialReversible induction of mitophagy by an optogenetic bimodular system
D’Acunzo, P., Strappazzon, F., Caruana, I., Meneghetti, G., Rita, A. D., Simula, L., Weber, G., Bufalo, F. D., Valle, L. D., Campello, S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09487-1 · Cited by 44
Tsushima, M., Liu, J., Hirao, W., Yamazaki, H., Tomita, H., & Itoh, K. (2019) · Archives of Pharmacal Research · doi:10.1007/s12272-019-01188-z · Cited by 42
“In particular, perinuclear clustering of depolarized mitochondria requires p62 and parkin (Okatsu et al. 2010).”
BackgroundKimura, Y., Fukushi, J., Hori, S., Matsuda, N., Okatsu, K., Kakiyama, Y., Kawawaki, J., Kakizuka, A., & Tanaka, K. (2013) · Genes to Cells · doi:10.1111/gtc.12103 · Cited by 41
“Mitochondria become ubiquitinated in Parkinexpressing cells after CCCP treatment (Okatsu et al. 2010).”
BackgroundSelf-citationHam, S. J., Lee, S. Y., Song, S., Chung, J.-R., Choi, S., & Chung, J. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.687319 · Cited by 40
“This sequence of mitophagy events can be visualized by immunostaining of p62/SQSTM1 and LC3B (18).”
BackgroundInfluentialPINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity
Koh, H., & Chung, J. (2012) · Molecules and Cells · doi:10.1007/s10059-012-0100-8 · Cited by 40
“However, other studies report that p62 and VDAC1 are dispensable for Parkin-induced mitophagy (Narendra et al., 2010b; Okatsu et al., 2010) and that the outer membrane protein degradation caused by the ubiquitin - proteasome system is critical for Parkin-mediated mitophagy (Chan et al.”
ResultEffect of p53 on mitochondrial morphology, import, and assembly in skeletal muscle
Saleem, A., Iqbal, S., Zhang, Y., & Hood, D. A. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00253.2014 · Cited by 40
Ready player one? Autophagy shapes resistance to photodynamic therapy in cancers
Duan, X., Chen, B., Cui, Y., Zhou, L., Wu, C., Yang, Z., Wen, Y., Miao, X., Li, Q., Xiong, L., et al. (2018) · APOPTOSIS · doi:10.1007/s10495-018-1489-0 · Cited by 43
SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation
Calvo‐Garrido, J., Maffezzini, C., Rosenberger, F. A., Clemente, P., Uhlin, E., Kele, M., Stranneheim, H., Lesko, N., Bruhn, H., Svenningsson, P., et al. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.01.023 · Cited by 44
Franci, L., Tubita, A., Bertolino, F. M., Palma, A., Cannino, G., Settembre, C., Rasola, A., Rovida, E., & Chiariello, M. (2022) · Aging Cell · doi:10.1111/acel.13620 · Cited by 40
Yurtsever, İ., Üstündağ, Ü. V., Ünal, İ., Ateş, P. S., & Emekli-Alturfan, E. (2022) · Drug and Chemical Toxicology · doi:10.1080/01480545.2020.1846549 · Cited by 39
“By accumulating in the outer membrane of the damaged mitochondria, PINK1 marks the damaged mitochondria for destruction (Ding et al. 2010, Okatsu et al. 2010).”
BackgroundUbiquitination Regulates the Morphogenesis and Function of Sperm Organelles
Nakamura, N. (2013) · Cells · doi:10.3390/cells2040732 · Cited by 42
“Parkin then ubiquitinates mitochondrial proteins at the outer mitochondrial membrane, such as voltage-dependent anion channel (VDAC) and mitofusins, thereby leading to the assembly of the autophagic machinery for mitophagy (p62 and LC3) [120,121].”
BackgroundInfluentialBus, C., Zizmare, L., Feldkaemper, M. P., Geisler, S., Zarani, M., Schaedler, A., Klose, F., Admard, J., Mageean, C. J., Arena, G., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101797 · Cited by 41
Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis
Basak, B., & Holzbaur, E. L. F. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169161 · Cited by 44
Foster, A. D., & Rea, S. L. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.284977 · Cited by 41
“…mitochondria (Geisler et al., 2010; Lee et al., 2010), other studies suggest that p62 is responsible for the aggregation and autophagosomal engulfment of mitochondria, but is not essential for their ultimate removal via mitophagy (Narendra et al., 2010; Okatsu et al., 2010; Matsumoto et al., 2015).”
BackgroundKoyano, F., Okatsu, K., Ishigaki, S., Fujioka, Y., Kimura, M., Sobue, G., Tanaka, K., & Matsuda, N. (2013) · Genes to Cells · doi:10.1111/gtc.12066 · Cited by 37
Self-citationMonoubiquitination of Ancient Ubiquitous Protein 1 Promotes Lipid Droplet Clustering
Lohmann, D., Spandl, J., Stevanovic, A., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072453 · Cited by 35
“Furthermore, it has been shown that p62/ SQSTM1 self-oligomerizes [63] and that mutation of amino acid residues of p62/SQSTM1 important for oligomerization attenuates the clustering of mitochondria [60].”
BackgroundRegulation of Autophagy by Metabolic and Stress Signaling Pathways in the Heart
Lee, Y., Lee, H.-Y., & Gustafsson, Å. B. (2012) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e318256cdd0 · Cited by 33
“Interestingly, p62 was not essential for Parkin-mediated mitophagy as p62 deficiency in cells did not prevent CCCP-mediated mitophagy.(88) We recently found that Bnip3-mediated mitochondrial autophagy was dependent on Parkin in cardiac myocytes and that Parkin deficient myocytes had reduced induction of autophagy in r…”
BackgroundNDP52 interacts with mitochondrial RNA poly(A) polymerase to promote mitophagy
Furuya, N., Kakuta, S., Sumiyoshi, K., Ando, M., Nonaka, R., Suzuki, A., Kazuno, S., Saiki, S., & Hattori, N. (2018) · EMBO Reports · doi:10.15252/embr.201846363 · Cited by 36
Self-citationde Araujo, B. P. R., Silva, L., Torresi, J. L. D. B., Siena, A., Valério, B. C. O., Brito, M. D., & Rosenstock, T. R. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02059-1 · Cited by 32
Common Principles and Specific Mechanisms of Mitophagy from Yeast to Humans
Kumar, R., & Reichert, A. S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094363 · Cited by 33
“Recently, it has been reported that p62 can promote PINK1–PARKIN independent mitophagy [90] by executing juxtanuclear clustering of damaged mitochondria that resemble p62-mediated ‘aggresomes’ of ubiquitinated aggregated proteins [91].”
BackgroundParkin and mitochondrial signalling
Connelly, E. M., Frankel, K. S., & Shaw, G. S. (2023) · Cellular Signalling · doi:10.1016/j.cellsig.2023.110631 · Cited by 38
Wilkins, J. M., McConnell, C., Tipton, P. A., & Hannink, M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.565549 · Cited by 33
“For example, increased mitochondrial fission has been linked to necrotic cell death (4), although mitochondrial clustering around the nucleus has been reported to occur prior to mitophagic turnover of damaged mitochondria (22, 23).”
BackgroundBcl-xL inhibits PINK1/Parkin-dependent mitophagy by preventing mitochondrial Parkin accumulation
Si, Y., Du, M., Yin, A., Mai, Z., Wang, Y., Zhao, M., Wang, X., & Chen, T. (2020) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2020.105720 · Cited by 32
Phospho-ubiquitin-PARK2 complex as a marker for mitophagy defects
Callegari, S., Oeljeklaus, S., Warscheid, B., Dennerlein, S., Thumm, M., Rehling, P., & Dudek, J. (2016) · Autophagy · doi:10.1080/15548627.2016.1254852 · Cited by 33
Multiple recycling routes: Canonical vs. non-canonical mitophagy in the heart
Moyzis, A. G., & Gustafsson, Å. B. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.09.034 · Cited by 33
Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA
Fermaintt, C. S., Takahashi‐Ruiz, L., Liang, H., Mooberry, S. L., & Risinger, A. L. (2021) · Molecular Pharmacology · doi:10.1124/molpharm.121.000297 · Cited by 33
“As previously shown for other microtubule destabilizers (Okatsu et al., 2010), we found that eribulin-treated cells acquired a somewhat fragmented mitochondrial phenotype, a feature not observed in paclitaxel-treated cells (Supplemental Fig.”
BackgroundCalderilla‐Barbosa, L., Seibenhener, M. L., Du, Y., Díaz-Meco, M. T., Moscat, J., Yan, J., Wooten, M. W., & Wooten, M. C. (2014) · Journal of Cell Science · doi:10.1242/jcs.152363 · Cited by 31
“The adaptor protein SQSTM1 (Okatsu et al., 2010) has also been implicated in aggresome formation by contributing to the transport of both ubiquitylated (Behl, 2011) and nonubiquitylated proteins (Watanabe and Tanaka, 2011).”
BackgroundZhang, D., Gao, C., Li, R., Zhang, L., & Tian, J. (2017) · Archives of Pharmacal Research · doi:10.1007/s12272-017-0899-9 · Cited by 31
Reidick, C., Magraoui, F. E., Meyer, H. E., Stenmark, H., & Platta, H. W. (2014) · Cancers · doi:10.3390/cancers7010001 · Cited by 31
“The accumulating ubiquitinated mitochondrial proteins attract the autophagy-receptor p62 [166,167], which simultaneously binds to ubiquitin and LC3, a protein present on growing phagophores [172].”
BackgroundGorgogietas, V. A., Tsialtas, I., Sotiriou, N., Laschou, V. C., Karra, A. G., Leonidas, D. D., Chrousos, G. P., Protopapa, E., & Psarra, A. G. (2018) · PubMed · Cited by 30
Jannuzzi, A. T., Arslan, S., Yılmaz, A. M., Sarı, G., Beklen, H., Méndez, L., Fedorova, M., Arğa, K. Y., Karademir-Yilmaz, B., & Alpertunga, B. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101502 · Cited by 31
“On the other hand, oxidative stress-induced mitochondrial depolarization results in perinuclear clustering of depolarized mitochondria and SQSTM1 is required for this process [61].”
BackgroundMalena, A., Pantic, B., Borgia, D., Sgarbi, G., Solaini, G., Holt, I. J., Spinazzola, A., Perissinotto, E., Sandri, M., Baracca, A., et al. (2016) · Autophagy · doi:10.1080/15548627.2016.1226734 · Cited by 31
Serum starvation induces anti-apoptotic cIAP1 to promote mitophagy through ubiquitination
Mukhopadhyay, S., Naik, P. P., Panda, P. K., Sinha, N., Das, D. N., & Bhutia, S. K. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.09.143 · Cited by 28
HIF‐1α Ameliorates Diabetic Neuropathic Pain via Parkin‐Mediated Mitophagy in a Mouse Model
He, J., Qin, Z., Chen, X., He, W., Li, D., Zhang, L., Le, Y., Xiong, Q., Zhang, B., & Wang, H. (2022) · BioMed Research International · doi:10.1155/2022/5274375 · Cited by 29
“The activated PINK1 then recruited Parkin to depolarize mitochondria [49] and then further connected with p62 and LC3 for ubiquitination degradation [50, 51].”
Parkinson's syndrome and Parkinson's disease in mitochondrial disorders
Finsterer, J. (2011) · Movement Disorders · doi:10.1002/mds.23651 · Cited by 28
“However, a detailed mechanism explaining how parkin recognizes damaged mitochondria and then catalyzes their ubiquitylation, so far has remained elusive.(42,47) There are indications, however, that parkin-catalyzed polyubiquitylation of depolarized mitochondria results in the clustering of mitochondria in the perinucl…”
BackgroundHirano, T., Suzuki, N., Ikenaka, Y., Hoshi, N., & Tabuchi, Y. (2021) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2021.115723 · Cited by 27
Macroautophagy and Mitophagy in Neurodegenerative Disorders: Focus on Therapeutic Interventions
Magalhães, J. D., Fão, L., Vilaça, R., Cardoso, S. M., & Rego, A. C. (2021) · Biomedicines · doi:10.3390/biomedicines9111625 · Cited by 29
Deubiquitinating Enzymes in Parkinson’s Disease
Chakraborty, J., & Ziviani, E. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00535 · Cited by 26
Dysregulation of autophagy in human follicular lymphoma is independent of overexpression of BCL-2
McCarthy, A., Marzec, J., Clear, A. J., Petty, R. D., Coutinho, R., Matthews, J., Wilson, A., Iqbal, S., Calaminici, M., Gribben, J. G., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2605 · Cited by 25
“A constitutive basal level of autophagy in normal tissue provides an important homeostatic, housekeeping function to survive stress, such as nutrient deprivation [21, 35].”
Marchesan, E., Nardin, A., Mauri, S., Bernardo, G., Chander, V., Paola, S. D., Chinellato, M., von Stockum, S., Chakraborty, J., Herkenne, S., et al. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-023-01251-9 · Cited by 29
Juncker, M. A., Kim, C., Reed, R. E., Haas, A. L., Schwartzenburg, J., & Desai, S. D. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166102 · Cited by 26
Drabik, K., Malińska, D., Piecyk, K., Dębska–Vielhaber, G., Vielhaber, S., Duszyński, J., & Szczepanowska, J. (2021) · Antioxidants · doi:10.3390/antiox10060938 · Cited by 24
“These proteins act at dif‐ ferent stages of mitochondrial removal by mitophagy, as follows: PINK1 mediates the la‐ beling of dysfunctional mitochondria directed for removal, while Beclin‐1 and LC3 coor‐ dinate autophagosome formation [26,27].”
BackgroundSUMOylation targeting mitophagy in cardiovascular diseases
Xiao, H., Zhou, H., Zeng, G., Mao, Z., Zeng, J., & Gao, A. (2022) · Journal of Molecular Medicine · doi:10.1007/s00109-022-02258-4 · Cited by 25
“Multiple studies have reported that mitochondrial fission is regulated by the mitochondrial membrane-bound E3 ligases MARCH5 and MULAN (MAPL) through the SUMOylation of dynamin-related protein (DRP1) mediated by SUMO1 [18,19].”
BackgroundRubin, B. P., & Debnath, J. (2010) · Autophagy · doi:10.4161/auto.6.8.13430 · Cited by 24
Gao, J., Qin, S., & Jiang, C. (2015) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmv044 · Cited by 24
“Parkin’s translocation to mitochondria dramatically changes the ubiquitination states of the mitochondrial proteome [8–10], and then those ubiquitinated mitochondria are recognized by autophagic adapter protein p62/SQSTM1 and finally degraded through autophagy [11,12].”
BackgroundMatić, I., Strobbe, D., Frison, M., & Campanella, M. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.03.021 · Cited by 23
K63-linked ubiquitylation induces global sequestration of mitochondria
Richard, T. J. C., Herzog, L. K., Vornberger, J., Rahmanto, A. S., Sangfelt, O., Salomons, F. A., & Dantuma, N. P. (2020) · Scientific Reports · doi:10.1038/s41598-020-78845-7 · Cited by 26
Molecular functions of autophagy adaptors upon ubiquitin-driven mitophagy
Yamano, K., & Kojima, W. (2021) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2021.129972 · Cited by 26
Liu, K., Zhou, X., Fang, L., Dong, J., Cui, L., Li, J., Meng, X., Zhu, G., Li, J., & Wang, H. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109200 · Cited by 24
Seibenhener, M. L., Zhao, T., Du, Y., Calderilla-Barbosa, L., Yan, J., Jiang, J., Wooten, M. W., & Wooten, M. C. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.04.006 · Cited by 22
PINK1 rendered temperature sensitive by disease-associated and engineered mutations
Narendra, D. P., Wang, C., Youle, R. J., & Walker, J. E. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt106 · Cited by 22
“Additional signs of Parkin activation by endogenous PINK1 following depolarization include the recruitment of the adaptor protein p62/SQSTM1 (6,23,24), which likely binds polyubiquitin chains attached to outer mitochondrial membrane proteins and causes mitochondrial clumping (23,24).”
BackgroundMitochondrial Homeostasis Molecules: Regulation by a Trio of Recessive Parkinson’s Disease Genes
Han, J., Kim, J., & Son, J. H. (2014) · Experimental Neurobiology · doi:10.5607/en.2014.23.4.345 · Cited by 21
“For example, the deletion of p62/SQSTM1 in MEF cells results in the gross loss of mitochondrial perinuclear clustering but does not inhibit mitochondrial clearance [31].”
BackgroundElevated autophagy and mitochondrial dysfunction in the Smith–Lemli–Opitz Syndrome
Chang, S., Ren, G., Steiner, R. D., Merkens, L. S., Roullet, J., Korade, Ž., DiMuzio, P. J., & Tulenko, T. N. (2014) · Molecular Genetics and Metabolism Reports · doi:10.1016/j.ymgmr.2014.09.005 · Cited by 21
“Parkin thus polyubiquitinates various mitochondrial surface proteins thereby targeting them for delivery to the autophagosome by aggregation and binding to P62's cargo recognition domain [23,40,41].”
Nargesi, A. A., Zhang, L., Tang, H. J., Jordan, K. L., Saadiq, I. M., Textor, S. C., Lerman, L. O., & Eirin, A. (2019) · Journal of Hypertension · doi:10.1097/hjh.0000000000002129 · Cited by 21
“Parkin has been also implicated in the transport of damaged mitochondria along microtubules to the perinuclear region [52].”
BackgroundLigeon, L., Temime‐Smaali, N., & Lafont, F. (2011) · Cellular Microbiology · doi:10.1111/j.1462-5822.2011.01628.x · Cited by 24
“The © 2011 Blackwell Publishing Ltd, Cellular Microbiology, 13, 1303–1311 alternative experiment in which non-invasive salmonella deliver the SopB to the host cytosol leads to engulfment of the bacteria in SCVs (Patel et al., 2009).”
BackgroundInfluentialUbiquitin signaling in PINK1/Parkin-dependent mitophagy
Okatsu, K., & Fukai, S. (2025) · The Journal of Biochemistry · doi:10.1093/jb/mvaf079 · Cited by 20
Self-citationParkin coordinates mitochondrial lipid remodeling to execute mitophagy
Lin, C., Yan, J., Kapur, M., Norris, K. L., Hsieh, C., Huang, D., Vitale, N., Lim, K., Guan, Z., Wang, X., et al. (2022) · EMBO Reports · doi:10.15252/embr.202255191 · Cited by 19
Cavaliere, V., Lombardo, T., Costantino, S. N., Kornblihtt, L. I., Álvarez, É., & Blanco, G. A. C. (2014) · European Journal of Cancer · doi:10.1016/j.ejca.2014.09.012 · Cited by 18
p62-Mediated mitochondrial clustering attenuates apoptosis induced by mitochondrial depolarization
Xiao, B., Deng, X., Lim, G. G.-Y., Zhou, W., Saw, W. T., Zhou, Z., Lim, K., & Tan, E. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.04.009 · Cited by 19
Congenital Disorders of Autophagy: What a Pediatric Neurologist Should Know
Ebrahimi‐Fakhari, D. (2017) · Neuropediatrics · doi:10.1055/s-0037-1608652 · Cited by 19
Miro1 functions as an inhibitory regulator of MFN at elevated mitochondrial Ca2+ levels
Fatiga, F. F., Wang, L., Hsu, T., Capuno, J. I., & Fu, C. (2021) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30138 · Cited by 20
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Hushmandi, K., Einollahi, B., Aow, R., Suhairi, S. B., Klionsky, D. J., Aref, A. R., Reiter, R. J., Makvandi, P., Rabiee, N., Xu, Y., et al. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107394 · Cited by 18
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Metadata
- Authors
- Okatsu, K., Saisho, K., Shimanuki, M., Nakada, K., Shitara, H., Sou, Y., Kimura, M., Sato, S., Hattori, N., Komatsu, M., Tanaka, K., & Matsuda, N.
- Affiliations
- Tokyo Metropolitan Institute of Medical Science (JP)
- University of Tsukuba (JP)
- Juntendo University (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Tanaka, Keiji
- Matsuda, Noriyuki
- ORCID
- Venue
- Genes to Cells
- Publisher
- Wiley
- Published
- 2010-07-17
- Volume
- 15
- Issue
- 8
- Pages
- 887-900
- ISSN
- 1356-9597 (ISSN-L)
- 1365-2443
- PMC
- PMC2970908
- OpenAlex
- W1904531393
- Semantic Scholar
- 0960aff7e7bc308a5932acbd9c26a685cf83635d
- Cited by
- 397
- References
- 54
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 9 · 2023: 9 · 2022: 11 · 2021: 22 · 2020: 27 · 2019: 24 · 2018: 33 · 2017: 25 · 2016: 27 · 2015: 40 · 2014: 43 · 2013: 30 · 2012: 43
- FWCI
- 20.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes to Cells (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (22650091)
- Japan Science and Technology Agency
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- p62, Parkin, PINK1, mitochondrial depolarization, ubiquitin-protein ligase, microtubule transport, mitochondrial quality control, mitochondrial degradation, aggresomes, Parkinson's disease, parkin mutations
- MeSH terms
- Sequestosome-1 Protein, Cell Nucleus, Cells, Cultured, DNA, Mitochondrial, HeLa Cells, Humans, Mitochondria, Protein Folding, Ubiquitin, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Ubiquitination, Biocatalysis
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