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 101–200 of 399
p62/SQSTM1 at the interface of aging, autophagy, and disease
Bitto, A., Lerner, C. A., Nacarelli, T., Crowe, E. P., Torres, C. A., & Sell, C. (2014) · AGE · doi:10.1007/s11357-014-9626-3 · Cited by 154
Franco-Iborra, S., Cuadros, T., Parent, A., Romero‐Giménez, J., Vila, M., & Perier, C. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-1154-0 · Cited by 150
Bit-by-bit autophagic removal of parkin-labelled mitochondria
Yang, J., & Yang, W. Y. (2013) · Nature Communications · doi:10.1038/ncomms3428 · Cited by 143
Lionaki, E., Markaki, M., Palikaras, K., & Tavernarakis, N. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.04.010 · Cited by 137
“melanogaster [124,136,137], although this model has been questioned by other studies showing that p62 is crucial for mitochondrial perinuclear aggregation rather than mitophagy [138,139].”
ResultCholine dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy
Park, S., Choi, S.-G., Yoo, S., Son, J. H., & Jung, Y. (2014) · Autophagy · doi:10.4161/auto.32177 · Cited by 137
Ivatt, R. M., Sanchez-Martinez, A., Godena, V. K., Brown, S., Ziviani, E., & Whitworth, A. J. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321207111 · Cited by 130
Miller, S., & Muqit, M. M. K. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.029 · Cited by 133
“Furthermore, conflicting findings have been reported for p62/sequestosome 1 (SQSTM1) as the adaptor for ubiquitinated mitochondria [26,62,75,78,118].”
Pilsl, A., & Winklhofer, K. F. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0902-3 · Cited by 131
Okatsu, K., Kimura, M., Oka, T., Tanaka, K., & Matsuda, N. (2015) · Journal of Cell Science · doi:10.1242/jcs.161000 · Cited by 133
“Degradation of the ubiquitylated mitochondria is thought to proceed through the proteasome (Yoshii et al., 2011) and autophagy, a process referred to as mitophagy (Narendra et al., 2008; Okatsu et al., 2010).”
BackgroundSelf-citationLoss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice
Sato, S., Uchihara, T., Fukuda, T., Noda, S., Kondo, H., Saiki, S., Komatsu, M., Uchiyama, Y., Tanaka, K., & Hattori, N. (2018) · Scientific Reports · doi:10.1038/s41598-018-21325-w · Cited by 125
Self-citationThe critical roles of mitophagy in cerebral ischemia
Tang, Y., Tian, H.-X., Yi, T., & Chen, H. (2016) · Protein & Cell · doi:10.1007/s13238-016-0307-0 · Cited by 134
Pancreatic β-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment
Bartolomé, A., Kimura-Koyanagi, M., Asahara, S., Guillén, C., Inoue, H., Teruyama, K., Shimizu, S., Kanno, A., García-Aguilar, A., Koike, M., et al. (2014) · Diabetes · doi:10.2337/db13-0970 · Cited by 125
“p62/SQSTM1 plays an important role in the recognition and grouping of mitochondria before their incorporation into the autophagic machinery (39,40).”
BackgroundMitochondrial DNA: Impacting Central and Peripheral Nervous Systems
Carelli, V., & Chan, D. C. (2014) · Neuron · doi:10.1016/j.neuron.2014.11.022 · Cited by 134
“Some autophagy adaptors, such as NBR1 and p62, bind to ubiquitin, but there are conflicting reports about their involvement in Parkin-mediated mitophagy (Geisler et al., 2010; Narendra et al., 2010a; Okatsu et al., 2010).”
BackgroundOrchestration of selective autophagy by cargo receptors
Adriaenssens, E., Ferrari, L., & Martens, S. (2022) · Current Biology · doi:10.1016/j.cub.2022.11.002 · Cited by 122
p62 Links β-adrenergic input to mitochondrial function and thermogenesis
Müller, T. D., Lee, S. J., Jastroch, M., Kabra, D. G., Stemmer, K., Aichler, M., Abplanalp, B., Ananthakrishnan, G., Bhardwaj, N. J., Collins, S., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci64209 · Cited by 127
“However, the analysis of p62-knockout cells does not support this notion, making this mitophagy function of p62 highly controversial at this moment (40–43).”
Haack, T. B., Ignatius, E., Calvo‐Garrido, J., Iuso, A., Isohanni, P., Maffezzini, C., Lönnqvist, T. R. I., Suomalainen, A., Gorza, M., Kremer, L. S., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.06.026 · Cited by 125
“seems to be indispensable for perinuclear clustering of depolarized mitochondria in a process of self-oligomerization.(3,18,19) Furthermore, TBK1-dependent phosphorylation of SQSTM1/p62 at Ser403 has been shown to promote the efficacy of autophagosomal engulfment of ubiquitinated mitochondria at an early phase of mito…”
BackgroundThe membrane peroxin PEX3 induces peroxisome-ubiquitination-linked pexophagy
Yamashita, S., Abe, K., Tatemichi, Y., & Fujiki, Y. (2014) · Autophagy · doi:10.4161/auto.29329 · Cited by 127
“SQSTM1 is required for peroxisome clustering In mammalian cells, SQSTM1 mediates the clustering of damaged mitochondria in parkin-mediated mitophagy, although it is dispensable for mitochondrial degradation.(37,38) Similarly, as described above, SQSTM1 colocalized with larger peroxisomal foci (Fig.”
Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up?
Grenier, K., McLelland, G., & Fon, E. A. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00100 · Cited by 124
“The ubiquitination of mitochondrial proteins by parkin has been suggested to recruit ubiquitin-binding adaptor proteins, such as p62/SQSTM1, to depolarized mitochondria (43, 57, 58).”
BackgroundAutophagosome dynamics in neurodegeneration at a glance
Wong, Y. C., & Holzbaur, E. L. F. (2015) · Journal of Cell Science · doi:10.1242/jcs.161216 · Cited by 117
“In addition, p62 is linked to ALS (Fecto et al., 2011) and regulates mitochondrial clustering through its Phox and Bem1p (PB1) oligomerization domain (Narendra et al., 2010a; Okatsu et al., 2010).”
BackgroundNguyen, T. D., Shaid, S., Vakhrusheva, O., Koschade, S. E., Klann, K., Thölken, M., Baker, F., Zhang, J., Oellerich, T., Sürün, D., et al. (2018) · Blood · doi:10.1182/blood-2018-02-833475 · Cited by 122
Molecular Regulation Mechanisms and Interactions Between Reactive Oxygen Species and Mitophagy
Fan, P., Xie, X.-H., Chen, C., Peng, X., Zhang, P., Yang, C. H., & Wang, Y. (2018) · DNA and Cell Biology · doi:10.1089/dna.2018.4348 · Cited by 122
“Although p62 plays an important role in the linkage of aggregated proteins with LC3 and subsequent mitophagy, the essential molecule for this process remains controversial (Komatsu et al. , 2007; Narendra et al. , 2010; Okatsu et al. , 2010).”
Anastasis: recovery from the brink of cell death
Tang, H. M., & Tang, H. L. (2018) · Royal Society Open Science · doi:10.1098/rsos.180442 · Cited by 117
Jian, F., Chen, D., Chen, L., Yan, C., Lü, B., Zhu, Y., Chen, S., Shi, A., Chan, D. C., & Song, Z. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.015 · Cited by 109
“These autophagy receptors then link LC3 to promote autophagosome formation (Geisler et al., 2010; Lazarou et al., 2015; Okatsu et al., 2010).”
BackgroundTundo, G. R., Sbardella, D., Santoro, A. M., Coletta, A., Oddone, F., Grasso, G., Milardi, D., Lacal, P. M., Marini, S., Purrello, R., et al. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107579 · Cited by 120
SQSTM1/p62 Interacts with HDAC6 and Regulates Deacetylase Activity
Yan, J., Seibenhener, M. L., Calderilla‐Barbosa, L., Díaz-Meco, M. T., Moscat, J., Jiang, J., Wooten, M. W., & Wooten, M. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076016 · Cited by 121
“In this role, p62 is involved in transport of both misfolded proteins and dysfunctional organelles to cellular degradation sites [18,19].”
BackgroundMechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond
Bayne, A. N., & Trempe, J. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03203-4 · Cited by 121
“A number of groups reported that the protein p62 is recruited to depolarized mitochondria [63, 129, 137, 138].”
BackgroundCaulfield, T. R., Fiesel, F. C., Moussaud-Lamodière, E. L., Dourado, D. F. A. R., Flores, S. C., & Springer, W. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003935 · Cited by 109
Geisler, S., Vollmer, S., Golombek, S., & Kahle, P. J. (2014) · Journal of Cell Science · doi:10.1242/jcs.146035 · Cited by 111
“Previously, it was shown that Parkin mediates the formation of K27- and K63-linked polyubiquitin chains on depolarized mitochondria (Geisler et al., 2010a; Narendra et al., 2010b; Okatsu et al., 2010).”
BackgroundInfluentialThe multifaceted role of mitochondria in autism spectrum disorder
Khaliulin, I., Hamoudi, W., & Amal, H. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02725-z · Cited by 128
“It has been suggested that this PTM of the mitochondrial proteins enables the recruitment of the autophagy adaptor p62, leading to the autophagosomal degradation of the damaged mitochondria [12, 278, 279].”
Mitochondrial Dynamics: The Intersection of Form and Function
Ferree, A. W., & Shirihai, O. S. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3573-0_2 · Cited by 113
Mitochondria Signaling Pathways in Allergic Asthma
Qian, L., Nasab, E. M., Athari, S. M., & Athari, S. S. (2022) · Journal of Investigative Medicine · doi:10.1136/jim-2021-002098 · Cited by 117
Cianfanelli, V., Zio, D. D., Bartolomeo, S. D., Nazio, F., Strappazzon, F., & Cecconi, F. (2015) · Journal of Cell Science · doi:10.1242/jcs.168153 · Cited by 105
“Next, these mitochondria are transported along microtubules to the perinuclear region, where they form rough aggregate structures termed mitoaggresomes (Lee et al., 2010; Okatsu et al., 2010; Vives-Bauza et al., 2010).”
BackgroundRegulation and function of mitophagy in development and cancer
Lu, H., Li, G., Liu, L., Feng, L., Wang, X., & Jin, H. (2013) · Autophagy · doi:10.4161/auto.26550 · Cited by 107
Proteolytic control of mitochondrial function and morphogenesis
Anand, R., Langer, T., & Baker, M. J. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.06.025 · Cited by 113
Boudoures, A. L., Saben, J. L., Drury, A. M., Scheaffer, S. M., Modi, Z. N., Zhang, W., & Moley, K. H. (2017) · Developmental Biology · doi:10.1016/j.ydbio.2017.04.005 · Cited by 104
Ubiquitin and Receptor-Dependent Mitophagy Pathways and Their Implication in Neurodegeneration
Fritsch, L. E., Moore, M. E., Sarraf, S. A., & Pickrell, A. M. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.10.015 · Cited by 106
“However, p62 does cause mitochondrial clustering in response to mitophagy, a role suggested to promote efficiency by collecting mitochondria targeted for removal at localized sites [72, 73].”
BackgroundMitochondrial Quality Control and Dynamics in Parkinson's Disease
McCoy, M. K., & Cookson, M. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4019 · Cited by 105
“Parkin expression is necessary to support depolarization-dependent K63 ubiquitination of mitochondria (39, 75), and mitochondria with parkin at the surface are sequestered and then degraded by autophagy.”
BackgroundWang, P., Wang, L., Lü, J., Hu, Y., Wang, Q., Li, Z., Cai, S., Liang, L., Guo, K., Xie, J., et al. (2019) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2019.06.005 · Cited by 102
Modulating Mitophagy in Mitochondrial Disease
Dombi, E., Mortiboys, H., & Poulton, J. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170616101741 · Cited by 100
“The authors also confirm previous findings that p62 is essential for the formation of perinuclear clusters of damaged mitochondria, however, dispensable for mitophagy [34, 35].”
Glucose starvation induces LKB1-AMPK-mediated MMP-9 expression in cancer cells
Endo, H., Owada, S., Inagaki, Y., Shida, Y., & Tatemichi, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-28074-w · Cited by 97
Mahalanobish, S., Dutta, S., Saha, S., & Sil, P. C. (2020) · Food and Chemical Toxicology · doi:10.1016/j.fct.2020.111588 · Cited by 99
Molecular signaling toward mitophagy and its physiological significance
Feng, D., Liu, L., Zhu, Y., & Chen, Q. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.03.034 · Cited by 99
“[59] demonstrated that VDAC is a substrate for Parkin and may be required for Parkin-dependent mitophagy, but other studies do not support the role of VDAC in mitophagy [73,74].”
BackgroundMitophagy and Parkinson's disease: Be eaten to stay healthy
de Vries, R. L. A., & Przedborski, S. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.07.008 · Cited by 96
Mitochondrial Dysfunction in Genetic Animal Models of Parkinson's Disease
Trancikova, A. K., Tsika, E., & Moore, D. J. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4200 · Cited by 94
“Parkin is normally a cytoplasmic protein but has been shown to translocate to depolarized or damaged mitochondria in numerous studies in Drosophila or mammalian cellular models (127, 132, 187).”
Mitophagy in the Pathogenesis of Liver Diseases
Ke, P. (2020) · Cells · doi:10.3390/cells9040831 · Cited by 91
“p62/SQSTM1 was also shown to activate PINK1/Parkin-dependent mitophagy by bridging the interaction between ubiquitinated voltage-dependent anion-selective channel 1 (VDAC1) on degrading mitochondria and LC3 on autophagosomal membranes [333] and mediating the clustering of depolarized mitochondria [334,335].”
BackgroundAlternative systems for misfolded protein clearance: life beyond the proteasome
Johnston, H. E., & Samant, R. S. (2020) · FEBS Journal · doi:10.1111/febs.15617 · Cited by 93
Shen, Y., Yang, J., Zhao, J., Xiao, C., Xu, C., & Xiang, Y. (2015) · Experimental Cell Research · doi:10.1016/j.yexcr.2015.04.010 · Cited by 92
Hematopoietic stem cell fate through metabolic control
Ito, K., & Ito, K. (2018) · Experimental Hematology · doi:10.1016/j.exphem.2018.05.005 · Cited by 98
Bloemberg, D., & Quadrilatero, J. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00261.2018 · Cited by 100
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Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice
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“R275W could not cluster damaged organelles or mediate their final degradation [Geisler et al., 2010; Narendra et al., 2010a; Okatsu et al., 2010].”
BackgroundParkin is a disease modifier in the mutant SOD1 mouse model of ALS
Palomo, G. M., Granatiero, V., Kawamata, H., Konràd, C., Kim, M. J., Arreguin, A. J., Zhao, D., Milner, T. A., & Manfredi, G. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201808888 · Cited by 88
“…and Parkin (Mouton-Liger et al , 2017), resulting in phosphorylated ubiquitin in the OMM (Kane et al , 2014; Kazlauskaite et al , 2014; Koyano et al , 2014), which in turn recruits autophagy receptors to the mitochondrial surface (Okatsu et al , 2010; Wong & Holzbaur, 2014; Lazarou et al , 2015).”
Mechanisms, pathophysiological roles and methods for analyzing mitophagy – recent insights
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“, 2016), but it is dispensable for mitophagy in MEFs and HeLa cells and may play a role in the clustering of damaged mitochondria (Narendra et al., 2010; Okatsu et al., 2010).”
BackgroundAutophagy inhibition uncovers the neurotoxic action of the antipsychotic drug olanzapine
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Self-citationReceptor protein complexes are in control of autophagy
Mijaljica, D., Nazarko, T. Y., Brumell, J. H., Huang, W., Komatsu, M., Prescott, M., Simonsen, A., Yamamoto, A., Zhang, H., Klionsky, D. J., et al. (2012) · Autophagy · doi:10.4161/auto.21332 · Cited by 87
Self-citationMitophagy in the pathogenesis and management of disease
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“76,77 78 – 81 Speci fi cally, NDP52 interacts with the ULK1 complex subunit FIP200, 78,79 whereas OPTN recruits ATG9 vesicles that are important for de novo autophagosome biogenesis 80,81 (Fig.”
A new robust fuzzy c-means clustering method based on adaptive elastic distance
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Molecular Insights into Parkinson's Disease
Rochet, J., Hay, B. A., & Guo, M. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00011-4 · Cited by 87
Yamaguchi, O., Murakawa, T., Nishida, K., & Otsu, K. (2016) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2016.03.010 · Cited by 86
“In this mitophagic process, p62 cooperates with Parkin for the elimination of damaged mitochondria [51].”
Lim, L., Jackson-Lewis, V. R., Wong, L. C., Shui, G., Goh, A. X., Kesavapany, S., Jenner, A. M., Fivaz, M. L., Przedborski, S., & Wenk, M. R. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.105 · Cited by 83
Mitochondrial function in vascular endothelial cell in diabetes
Pangare, M., & Makino, A. (2012) · Journal of Smooth Muscle Research · doi:10.1540/jsmr.48.1 · Cited by 87
“Ubiquitinated mitochondrial proteins by Parkin interact with the autophagy adaptor p62, and subsequently lead to the autophagosomal degradation of the mitochondria (Geisler et al., 2010; Okatsu et al., 2010) (Fig.”
BackgroundMitochondrial dismissal in mammals, from protein degradation to mitophagy
Campello, S., Strappazzon, F., & Cecconi, F. (2013) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2013.11.010 · Cited by 88
“Then, ubiquitylated mitochondria recruit ubiquitin-binding adaptor proteins, such as p62/SQSTM1 [110,115,116].”
BackgroundA role for sequestosome 1/p62 in mitochondrial dynamics, import and genome integrity
Seibenhener, M. L., Du, Y., Díaz-Meco, M. T., Moscat, J., Wooten, M. C., & Wooten, M. W. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.11.004 · Cited by 85
“p62 is known to be mitochondrially associated under stress conditions [12], including oxidative stress [37].”
Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice
Rogers, R. S., Tungtur, S., Tanaka, T., Nadeau, L. L., Badawi, Y., Wang, H., Ni, H.-M., Ding, W.-X., & Nishimune, H. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00473 · Cited by 83
“…protein 1 (VDAC1; Geisler et al., 2010). p62/SQSTM1 has a ubiquitin binding domain at the C-terminus that recognizes ubiquitinated mitochondrial proteins, accumulates to depolarized mitochondria, and recruits LC3 to mitochondria to induce mitophagy (Geisler et al., 2010; Okatsu et al., 2010).”
BackgroundInfluentialWeil, R., Laplantine, E., Curic, S., & Génin, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01243 · Cited by 83
Structure and function of p62/SQSTM1 in the emerging framework of phase separation
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Mitochondrial Dynamics and Parkinson's Disease: Focus on Parkin
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“Indeed, K63 polyubiquitin modification of several mitochondrial substrates takes place following CCCP-induced uncoupling (23, 68).”
Corti, O., & Brice, A. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.11.002 · Cited by 79
“Ubiquitylated OMM proteins may be recognized by the ubiquitin-binding adaptor protein p62 which binds the LC3 family of autophagosomal proteins, but ubiquitin on the OMM does not signal for mitophagy and p62 is dispensable for this process [29,30].”
Exploring new pathways of neurodegeneration in ALS: The role of mitochondria quality control
Palomo, G. M., & Manfredi, G. (2014) · Brain Research · doi:10.1016/j.brainres.2014.09.065 · Cited by 81
Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain mutant
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“While knockdown of p62 in U2OS cells abolishes mitophagy, mitophagic clearance of damaged mitochondria is not inhibited in p62 knockout MEFs (Lee et al. , 2010b; Okatsu et al. , 2010).”
Mitochondrial hexokinase HKI is a novel substrate of the Parkin ubiquitin ligase
Okatsu, K., Iemura, S., Koyano, F., Go, E., Kimura, M., Natsume, T., Tanaka, K., & Matsuda, N. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.10.041 · Cited by 81
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Self-citationMitochondria Autophagy in Yeast
Kanki, T., Klionsky, D. J., & Okamoto, K. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3762 · Cited by 77
“This step remains controversial, as it has been reported that p62 knockout mouse embryonic fibroblasts show wild-type levels of mitophagy (69).”
Nicoletti, V., Palermo, G., Prete, E. D., Mancuso, M., & Ceravolo, R. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.636506 · Cited by 75
Mitochondrial quality control in the diabetic heart
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Select E2 enzymes differentially regulate parkin activation and mitophagy
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“The observed mitochondrial morphology and distribution upon knockdown of UBE2N is indeed phenocopied by overexpression of a K63R ubiquitin variant or by knockdown of the cognate ubiquitin adaptor p62 (Geisler et al., 2010; Narendra et al., 2010a; Okatsu et al., 2010).”
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Mitophagy Contributes to the Pathogenesis of Inflammatory Diseases
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Sirtuin 3 silencing impairs mitochondrial biogenesis and metabolism in colon cancer cells
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PINK1-dependent mitophagy is driven by the UPS and can occur independently of LC3 conversion
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“This finding is partly consistent with previous studies (18, 19, 55).”
ResultSelf-citationMitophagy in hematopoietic stem cells
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A Mechanistic Review of Mitophagy and Its Role in Protection against Alcoholic Liver Disease
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“currently controversial because some have shown it is required for mitophagy [110,117], while others have shown that it is not [118,119].”
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Autophagy, reactive oxygen species and the fate of mammalian cells
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“It is recruited to depolarized mitochondria in PINK1/parkin-expressing cells [184].”
Background
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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