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.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
0 of 37 cited sources checked · 0 supported · 0 flagged
- Findingcitation
K161N, K211N and T240R Parkin mutations inhibit mitochondrial clustering by severely compromising mitochondrial localization of Parkin.
“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.”
Quote in the paperSubstantial claim - Findingown data
Endogenous p62 is mainly localized throughout the cytosol under steady-state conditions in HeLa cells, irrespective of Parkin presence.
“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).”
Quote in the paperNot a substantial claim - Findingown data
Parkin-catalyzed K63-linked polyubiquitylation of depolarized mitochondria results in ubiquitylated mitochondria being transported along microtubules to cluster in the perinuclear region.
“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.”
Quote in the paperSubstantial claim - Findingown data
p62 is recruited to depolarized mitochondria after Parkin-directed ubiquitylation.
“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)”
Quote in the paperSubstantial claim - Also stated in: § p62/SQSTM1 is not essential for mitochondrial degradation · plain
- Findingown data
Pathogenic mutations of Parkin interfere with perinuclear clustering of depolarized mitochondria.
“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”
Quote in the paperSubstantial claim - Also stated in: § Various pathogenic mutations of Parkin impede mitochondrial clustering · plain
- Findingown data
Deletion of p62 in mouse embryonic fibroblasts results in a gross loss of mitochondrial perinuclear clustering.
“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).”
Quote in the paperSubstantial claim - Also stated in: § p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria · plain
- Findingown data
Treatment with microtubule polymerization inhibitors nocodazole or colchicine dissipates perinuclear mitochondrial clusters in Parkin-expressing HeLa cells.
“After treatment with nocodazole (10 μg/mL) or colchicine (50 μg/mL), the perinuclear mitochondria clusters dissipated (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data
Mitochondria later concentrate to the perinuclear region at t > 4 h after CCCP treatment.
“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).”
Quote in the paperSubstantial claim - Findingown data
Deletion of p62 in mouse embryonic fibroblasts does not hinder mitochondrial degradation.
“but did not hinder mitochondrial degradation.”
Quote in the paperSubstantial claim - Findingown data
Parkin ubiquitylates damaged mitochondria mainly via K63-linked polyubiquitylation.
“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).”
Quote in the paperSubstantial claim - Findingown data
Treatment with actin polymerization inhibitors latrunculin A/B has no effect on mitochondrial perinuclear clustering.
“In contrast, treatment with latrunculin A/B, which prevents actin polymerization, had no effect on the mitochondrial perinuclear clustering (not shown).”
Quote in the paperSubstantial claim - Findingown data
K63-linked ubiquitylation on mitochondria depends on the E3 activity of Parkin.
“K63-linked ubiquitylation on mitochondria depends on the E3 activity of Parkin. K63-linked ubiquitylation signal disappeared when the catalytically dead T415N and G430D mutations were introduced into Parkin.”
Quote in the paperSubstantial claim - Findingown data
In wild-type MEFs, quantity of mitochondrial 12s ribosomal RNA gene decreased to 62 ± 4% after CCCP treatment.
“we found that the quantity of 12s ribosomal RNA gene was decreased to 62 ± 4% after CCCP treatment, whereas the Atg7 knockout compensated for the decease by restoring the level to 95 ± 13%, suggesting that the reduction in mitochondrial DNA reflects Parkin-dependent mitophagy.”
Quote in the paperSubstantial claim - Findingcitation
Clearance of depolarized mitochondria is considerably impeded in Atg7 KO MEFs after CCCP treatment for 24 h.
“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. 6A and (Matsuda et al. 2010)].”
Quote in the paperSubstantial claim - Findingown data
Parkin is selectively recruited to mitochondria after CCCP treatment in both p62+/+ and p62−/− MEFs at t = 4 h.
“Parkin was selectively recruited to the mitochondria after CCCP treatment in both p62+/+ and p62−/− MEFs at t = 4 h (Fig. 5B and data not shown).”
Quote in the paperSubstantial claim - Findingown data
The signals generated by Apu3 and HWA4C4 disappeared with E3-inactivated mutations of Parkin.
“We confirmed that the signals generated by Apu3 and HWA4C4 disappeared with E3-inactivated mutations of Parkin (Fig. 1F and not shown).”
Quote in the paperSubstantial claim - Findingown data
Some mitochondria in juxtanuclear clusters are malformed with disintegration of cristae structures.
“Some mitochondria were malformed with disintegration of cristae structures indicated by black staining (Fig. 5C, arrowheads).”
Quote in the paperNot a substantial claim - Findingown data
Re-introduction of GFP-tagged p62 complements perinuclear clustering of depolarized mitochondria in p62−/− MEFs.
“Re-introduction of GFP-tagged p62 (Ichimura et al. 2008) complemented the perinuclear clustering of depolarized mitochondria in p62−/− MEFs (Fig. 7), confirming that the observed defects were caused by the loss of p62.”
Quote in the paperSubstantial claim - Findingown data
Atg7 knockout restored mitochondrial 12s rRNA gene level to 95 ± 13% after CCCP treatment.
“whereas the Atg7 knockout compensated for the decease by restoring the level to 95 ± 13%, suggesting that the reduction in mitochondrial DNA reflects Parkin-dependent mitophagy.”
Quote in the paperSubstantial claim - Findingown data
CCCP treatment of p62 KO MEFs promoted degradation of mitochondrial DNA to 43 ± 2%, comparable to wild-type MEFs.
“Furthermore, CCCP treatment of p62 KO MEFs promoted the degradation of mitochondrial DNA (43 ± 2%) comparable to that of wild-type MEFs (Fig. 6D), again implying that mitochondrial degradation occurs in p62−/− MEFs.”
Quote in the paperSubstantial claim - Findingown data
p62 deletion accelerates Parkin-dependent mitochondrial degradation in MEFs.
“Contrary to our expectations, immunocytochemistry experiments at 12, 16, 20 and 24 h showed that p62 deletion did not inhibit but rather accelerated Parkin-dependent mitochondrial degradation (Fig. 6A–C).”
Quote in the paperSubstantial claim - Findingown data
p62 is rapidly recruited to mitochondria only in Parkin-expressing cells after CCCP treatment for 1 h.
“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).”
Quote in the paperSubstantial claim - Findingreasoning
Depolarized mitochondria are recognized by p62.
“recognized by p62”
Quote in the paperSubstantial claim - Findingnone given
Depolarized mitochondria are ubiquitylated by Parkin.
“Depolarized mitochondria were ubiquitylated by Parkin”
Quote in the paperSubstantial claim - Findingreasoning
Depolarized mitochondria are transported via microtubules to aggregate within a juxtanuclear region.
“transported via microtubules to aggregate within a juxtanuclear region”
Quote in the paperSubstantial claim - Findingown data
Parkin-dependent mitochondrial degradation was not hindered in p62 KO (p62−/−) MEFs.
“we showed by immunocytochemistry and quantitative analysis of mitochondrial DNA that Parkin-dependent mitochondrial degradation was not hindered in p62 KO (p62−/−) MEFs (Figs 6,7).”
Quote in the paperSubstantial claim - Findingown data
Perinuclear clustering of depolarized mitochondria was severely inhibited by p62 deletion.
“we realized that perinuclear clustering of depolarized mitochondria was severely inhibited by p62 deletion”
Quote in the paperSubstantial claim - Findingown data
In p62−/− MEFs, the W340A mutant did complement the dispersion of mitochondria.
“When introduced into p62−/− MEFs, the K7A/D69A mutant was unable to complement the dispersion of mitochondria, whereas the W340A mutant did (Fig. 7).”
Quote in the paperSubstantial claim - Findingown data
In p62−/− MEFs, the K7A/D69A mutant was unable to complement the dispersion of mitochondria.
“When introduced into p62−/− MEFs, the K7A/D69A mutant was unable to complement the dispersion of mitochondria, whereas the W340A mutant did (Fig. 7).”
Quote in the paperSubstantial claim - Findingown data
A delay in mitochondrial degradation was observed in p62−/− MEFs complemented with the p62 mutant W340A.
“Interestingly, a delay in mitochondrial degradation was observed in p62−/− MEFs complemented with the p62 mutant W340A (Fig. 7B)”
- Also stated in: § p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria · plain
“mitochondrial degradation was impaired in p62−/− MEFs complemented with the p62 W340A mutant.”
Quote in the paperSubstantial claim - Also stated in: § p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria · plain
- Interpretationown data
Ubiquitylation catalyzed by Parkin is required for mitochondrial clustering.
“These results suggest that ubiquitylation catalyzed by Parkin is required for mitochondrial clustering.”
Quote in the paperSubstantial claim - Interpretationown data
Transport of depolarized mitochondria to the perinuclear region is microtubule dependent.
“These results suggest that the transport of depolarized mitochondria to the perinuclear region is microtubule dependent and are in agreement with a recent report by Przedborski’s group (Vives-Bauza et al. 2010).”
Quote in the paperSubstantial claim - Interpretationown data
p62 is required for ubiquitylation-dependent clustering of damaged mitochondria.
“Thus, p62 is required for ubiquitylation-dependent clustering of damaged mitochondria, which resembles p62-mediated ‘aggresome’ formation of misfolded/unfolded proteins after ubiquitylation.”
- Also stated in: § p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria · plain
“p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria”
Quote in the paperSubstantial claim - Also stated in: § p62/SQSTM1 is necessary for perinuclear clustering of damaged mitochondria · plain
- Premisecitation
Linkage-specific anti-ubiquitin antibodies Apu2, Apu3 and HWA4C4 can determine the linkage without overproduction of mutant ubiquitin.
“To address this issue, we used linkage-specific anti-ubiquitin antibodies Apu2, Apu3 and HWA4C4 (Newton et al. 2008; Wang et al. 2008) that can determine the linkage without overproduction of mutant ubiquitin.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Newton et al. 2008
Not checked in the free run.
- cites Wang et al. 2008
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- Premisecitation
R275W and C352G Parkin mutations have intact E3 activity against a pseudo-substrate.
“Because ubiquitin-ligase (E3) activity against a pseudo-substrate (i.e., the MBP moiety of the MBP-fused Parkin in vitro and the GFP moiety of the GFP-Parkin in cell) was intact in these Parkin mutations (Hampe et al. 2006; Matsuda et al. 2006, 2010)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Hampe et al. 2006
Not checked in the free run.
- cites Matsuda et al. 2006, 2010
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- Premisecitation
Loss of mitochondrial membrane potential stabilizes PINK1 on damaged mitochondria.
“a loss in mitochondrial membrane potential stabilizes PINK1 on damaged mitochondria 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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Matsuda et al. 2010
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- cites Narendra et al. 2010
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- Interpretationown data
Ubiquitylation-catalyzed Parkin is required for recruitment of p62 onto depolarized mitochondria.
“suggesting that ubiquitylation-catalyzed Parkin is required for the recruitment of p62 onto depolarized mitochondria.”
Quote in the paperSubstantial claim - Interpretationown data
Observed defects in p62−/− MEFs were caused by loss of p62.
“confirming that the observed defects were caused by the loss of p62.”
Quote in the paperSubstantial claim - Interpretationown data
Depolarized mitochondria are degraded by the autophagic and lysosomal pathway in p62−/− MEFs.
“showing that depolarized mitochondria were indeed degraded by the autophagic and lysosomal pathway in p62−/− MEFs.”
Quote in the paperSubstantial claim - Interpretationown data
The reduction in mitochondrial DNA reflects Parkin-dependent mitophagy.
“suggesting that the reduction in mitochondrial DNA reflects Parkin-dependent mitophagy.”
Quote in the paperSubstantial claim - Study design and conductown data
Immunocytochemistry using anti-p62 antibody confirmed that endogenous p62 was indeed lost in p62−/− MEFs.
“Immunocytochemistry using an anti-p62 antibody confirmed that endogenous p62 was indeed lost in p62−/− MEFs (Fig. 5A, right panel).”
Quote in the paperSubstantial claim - Premisecitation
K161N, K211N and T240R Parkin mutations severely compromise mitochondrial localization of Parkin.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Geisler et al. 2010
Not checked in the free run.
- cites Matsuda et al. 2010
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- cites Narendra et al. 2010
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- Premisecitation
Damaged mitochondria are subjected to retrograde transport along microtubules toward the cell body.
“damaged mitochondria are subjected to retrograde transport along microtubules toward the cell body”
Quote in the paperSubstantial claim0 of 1 sources checked- cites MacAskill & Kittler 2010
Not checked in the free run.
- Interpretationcitation
Mitochondria are a key component of the early phase in the biogenesis of the Lewy body.
“These results suggest that mitochondria are a key component of the early phase in the biogenesis of the Lewy body”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Gai et al. (2000)
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- cites Bedford et al. (2008)
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- Interpretationreasoning
Functional redundancy resolves the discrepancy between the results and prior work.
“We think a key idea to resolve this discrepancy is functional redundancy.”
Quote in the paperSubstantial claim - Interpretationcitation
p62 is a plausible factor that links Parkin-catalyzed ubiquitylation with mitochondrial degradation via autophagy.
“and thus p62 is a plausible factor that links Parkin-catalyzed ubiquitylation with mitochondrial degradation via autophagy.”
Quote in the paperSubstantial claim - Premisecitation
In axons, microtubules are oriented with their plus ends toward the periphery.
“In axons, microtubules are oriented with their plus ends toward the periphery”
Quote in the paperSubstantial claim0 of 1 sources checked- cites MacAskill & Kittler 2010
Not checked in the free run.
- Interpretationown data
p62 is involved in perinuclear clustering of depolarized mitochondria.
“showing that p62 is involved in this process.”
Quote in the paperSubstantial claim - Interpretationown data
p62 is involved in Parkin-mediated mitophagy.
“suggesting that p62 is involved in Parkin-mediated mitophagy.”
- Also stated in: § Function of p62 in the degradation of depolarized mitochondria · hedged
“implying the involvement of p62 in Parkin-mediated mitophagy”
Quote in the paperSubstantial claim- Rests on an assumption: The p62 W340A mutant cannot interact with LC3.
- Also stated in: § Function of p62 in the degradation of depolarized mitochondria · hedged
- Interpretationown data
p62 is not involved in Parkin-mediated mitophagy.
“These results, while admittedly not conclusive, seemingly suggest that p62 is not involved in Parkin-mediated mitophagy.”
Quote in the paperSubstantial claim - Premisecitation
Several intracellular proteins such as NBR1, Alfy and BAG3 might be able to link Parkin-catalyzed ubiquitylation to autophagic degradation.
“Even when p62 is lost, several intracellular proteins such as NBR1, Alfy and BAG3 (Kirkin et al. 2009) might be able to link Parkin-catalyzed ubiquitylation to autophagic degradation”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kirkin et al. 2009
Not checked in the free run.
- May combine two claims. 14
- Classified as probably not a substantial claim. 17
May combine two claims.
Findingown dataR275W and C352G Parkin mutations associate with depolarized mitochondria but severely inhibit mitochondrial ubiquitylation and juxtanuclear clustering.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationPerinuclear transport and clustering of mitochondria are Parkin dependent, observed only in Parkin-expressing HeLa cells that lack endogenous Parkin.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataParkin quickly moves to depolarized mitochondria and ubiquitylates them at t = 1 h after CCCP treatment.
“In mitochondria fragmented with the mitochondrial uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), Parkin quickly moved to depolarized mitochondria and ubiquitylated them (t = 1 h).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn wild-type MEFs, p62 is selectively recruited to mitochondria after CCCP treatment at t = 4 h, and depolarized mitochondria later cluster in perinuclear region at t > 12 h.
“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).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMitochondrial localization of p62 is only observed in Parkin-expressing cells and disappears when Parkin mutants deficient in substrate recognition or E3 activity (R275W, C352G, T415N, G430D) are introduced.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataJuxtanuclear-clustered mitochondria aggregate in grape-like clusters and are not fused to each other to make single large mitochondrion.
“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).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationPINK1 recruits Parkin from the cytoplasm to depolarized mitochondria, which then undergo Parkin-catalyzed ubiquitylation.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Narendra et al. 2008, 2010
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- cites Geisler et al. 2010
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- cites Matsuda et al. 2010
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Classified as probably not a substantial claim.
PremisecitationPINK1 and Parkin cooperate to ubiquitylate mitochondria with low membrane potentials.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Narendra et al. 2008, 2010
Not checked in the free run.
- cites Geisler et al. 2010
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- cites Matsuda et al. 2010
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationParkin has the potential to catalyze multiple monoubiquitylation, Lys-48-linked polyubiquitylation and Lys-63-linked polyubiquitylation.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Lim 2007
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- cites Matsuda & Tanaka 2010
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Study design and conductown dataStaining with single antibodies alone indicated that merged data were not derived from channel crosstalk.
“Staining with single antibodies alone indicated that the merged data described earlier were not derived from channel crosstalk (Fig. S1 in Supporting Information).”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitationp62 can interact with both ubiquitin and the autophagic machinery LC-3.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Bjorkoy et al. 2005
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- cites Komatsu et al. 2007
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- cites Pankiv et al. 2007
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Classified as probably not a substantial claim. May combine two claims.
PremisecitationBafilomycin A1 is an inhibitor of vacuolar-type H+-ATPase that prevents autophagosome-lysosome fusion and/or intralysosomal degradation.
“bafilomycin A1 (an inhibitor of vacuolar-type H+-ATPase that prevents autophagosome-lysosome fusion and/or intralysosomal degradation)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mizushima et al. 2010
Not checked in the free run.
May combine two claims.
Study design and conductown dataThe linkage specificity of anti-ubiquitin antibodies was confirmed by MALDI-TOF mass spectrometry and immunoblotting showed high specificity.
“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).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationOverproduction of mutant ubiquitin can change the ubiquitylation linkage.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Pickart & Raasi 2005
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- cites Saeki et al. 2009
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPINK1 functions upstream of Parkin, because forced overexpression of Parkin rescues loss-of-function phenotypes of PINK1 but not vice versa.
“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).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Clark et al. 2006
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- cites Park et al. 2006
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- cites Yang et al. 2006
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Study design and conductnone givenLys 48- or Lys 63-linked polyubiquitin chain was used as a positive control to check the specificity of linkage-specific anti-ubiquitin antibodies.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMitochondria are delivered to areas of the axon where metabolic demand is high, such as synapses, active growth cones and branches.
“mitochondria are delivered to areas of the axon where metabolic demand is high, such as synapses, active growth cones and branches (Hollenbeck & Saxton 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hollenbeck & Saxton 2005
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Study design and conductnone givenUracil DNA Glycosylase was added during PCR to prevent carry-over contamination.
“To prevent carry-over contamination, 0.5 unit of Uracil DNA Glycosylase (Invitrogen) was added during PCR”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningComplete 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).”
Quote in the paperSubstantial claim- Rests on an assumption: Complete disruption of p62 cannot cause this type of titration and thus cannot confer the dominant effect.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationMitochondrial clustering might be involved in Lewy body biogenesis.
“and thus mitochondrial clustering might be involved in this process.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationMitochondria-dedicated selective autophagy (mitophagy) is considered essential for clearance of impaired mitochondria.
“with mitochondria-dedicated selective autophagy (termed mitophagy) considered to be essential for this clearance pathway (Narendra et al. 2008; Twig et al. 2008).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Narendra et al. 2008
Not checked in the free run.
- cites Twig et al. 2008
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSamples were prepared in triplicate for each condition.
“samples were prepared in triplicate for each condition.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataOligomerization of p62 but not interaction with LC3 is essential for the mitochondrial clustering triggered by Parkin.
“These results suggest that oligomerization of p62 but not interaction with LC3 is essential for the mitochondrial clustering triggered by Parkin.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lamark et al. 2003
Not checked in the free run.
- Rests on an assumption: The K7A/D69A double mutation in the PB1 domain abolishes p62 oligomerization.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe defect in p62−/− MEFs is concealed by other functionally redundant protein(s).
“The defect in p62−/− MEFs, however, is concealed by other functionally redundant protein(s) (see Discussion).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kirkin et al. 2009
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningMethodological differences (p62 knockout MEFs vs p62 siRNA in HeLa cells) may account for the conflicting observations between this study and Geisler et al.
“methodological differences (i.e. we used p62 knockout MEFs whereas they used p62 siRNA in HeLa cells) may account for the conflicting observations”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Geisler et al. (2010)
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe p62 W340A mutant competes for certain common factor(s) with functionally redundant protein(s), and thus has a dominant effect.
“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”
Quote in the paperSubstantial claim- Rests on an assumption: The p62 W340A mutant cannot interact with LC3.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationreasoningAggresome and mitochondrial clustering have something in common.
“The similarity between aggresome and mitochondrial clustering, although superficial at the moment, suggests that the two ubiquitin-mediated cytoprotective events have something in common.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningMitochondrial clustering is reminiscent of aggresome formation.
“This series of events is reminiscent of aggresome formation”
Quote in the paperNot a substantial claim
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?
This results in the preferential degradation of mitochondrial outer membrane proteins by the proteasome, while inner membrane proteins and mitochondrial DNA remain intact.
“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]
In Results, under “p62/SQSTM1 is not essential for mitochondrial degradation” (page unavailable), the paper reports that mitochondrial DNA decreased after CCCP treatment, contrary to the claim that it remained intact. It identifies autophagic and lysosomal degradation of depolarized mitochondria; it does not report preferential proteasomal degradation of outer-membrane proteins while inner-membrane proteins remain intact. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredDuring mitochondrial degradation in cultured cells, depolarized mitochondria cluster with p62.
“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]
Depolarized mitochondria are ubiquitylated by Parkin, recognized by p62, transported via microtubules to aggregates, and degraded by autophagy.
“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]
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.
Reported percentage change contradicts inhibited mitochondrial clearance
MinorThe text says p62 knockdown inhibited clearance, but then says the proportion of cells with uncleared mitochondria decreased from 85% to 20% after knockdown. A decrease in uncleared mitochondria indicates greater clearance, not inhibited clearance.
“They showed that knockdown of p62 in HeLa cells dramatically inhibited the final clearance of damaged mitochondria”
“cells with uncleared mitochondria decreased from 85% to 20% with p62 siRNA treatment.”
Eight Parkin mutations are claimed, but only seven are listed
MinorThe parenthetical list contains seven mutations, not eight. K211N is discussed immediately afterward as an analyzed mutation but is absent from the list.
“HA-Parkin mutants harboring one of eight pathogenic mutations (R42P, K161N, T240R, R275W, C352G, T415N and G430D; Fig. 3A)”
“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.”
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× · see citing works
“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 · see citing works
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× · see citing works
“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× · see citing works
“…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 <i>PINK1</i>
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× · see citing works
“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 · see citing works
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× · see citing works
“…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× · see citing works
“…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× · see citing works
“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 <i>Atg7</i> -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× · see citing works
“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-citationAggresomes: A Cellular Response to Misfolded Proteins
Johnston, J. A., Ward, C. L., & Kopito, R. R. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.143.7.1883 · Cited by 2,148 · cited 2× · see citing works
“…concentrated into proteinacious inclusion bodies and ⁄ or recognized by HDAC6 to be transported along microtubles, organized into a perinuclear aggregation (an aggresome) and sometimes degraded by autophagy (Johnston et al. 1998; Garcia-Mata et al. 1999; Olzmann et al. 2007; Kirkin et al. 2009).”
BackgroundHomeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
Komatsu, M., Waguri, S., Koike, M., Sou, Y.-S., Ueno, T., Hara, T., Mizushima, N., Iwata, J.-I., Ezaki, J., Murata, S., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.035 · Cited by 2,124 · cited 5× · see citing works
“…of p62 in Parkin-mediated mitochondrial degradation. 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…”
BackgroundInfluentialSelf-citationFamilial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
Shimura, H., Hattori, N., Kubo, S.-I., Mizuno, Y., Asakawa, S., Minoshima, S., Shimizu, N., Iwai, K., Chiba, T., Tanaka, K., et al. (2000) · Nature Genetics · doi:10.1038/77060 · Cited by 2,024 · cited 1× · see citing works
“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-citationMatsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C. A., Sou, Y.-S., Saiki, S., Kawajiri, S., Sato, F., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200910140 · Cited by 1,969 · see citing works
Self-citationDrosophila pink1 is required for mitochondrial function and interacts genetically with parkin
Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., Yoo, S. J., Hay, B. A., & Guo, M. (2006) · Nature · doi:10.1038/nature04779 · Cited by 1,788 · cited 1× · see citing works
“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).”
BackgroundMitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin
Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., Bae, E., Kim, J., Shong, M., Kim, J.-M., et al. (2006) · Nature · doi:10.1038/nature04788 · Cited by 1,705 · cited 1× · see citing works
“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).”
BackgroundKinesin and Dynein Superfamily Proteins and the Mechanism of Organelle Transport
Hirokawa, N. (1998) · Science · doi:10.1126/science.279.5350.519 · Cited by 1,689 · cited 2× · see citing works
“Mitochondrial clustering is microtubule dependent Within the cell, many organelles including mitochondria are transported along microtubules, which function as intracellular railways (Hirokawa 1998).”
BackgroundPINK1-dependent recruitment of Parkin to mitochondria in mitophagy
Vives-Bauza, C., Zhou, C., Huang, Y., Cui, M., de Vries, R. L. A., Kim, J., May, J., Tocilescu, M. A., Liu, W., Ko, H. S., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911187107 · Cited by 1,616 · cited 5× · see citing works
“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).”
BackgroundResultInfluentialThemes and variations on ubiquitylation
Weissman, A. M. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35056563 · Cited by 1,472 · see citing works
A Role for Ubiquitin in Selective Autophagy
Kirkin, V., McEwan, D. G., Novak, I., & Đikić, I. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.04.026 · Cited by 1,227 · cited 12× · see citing works
“7), confirming that the observed defects were caused by the loss of p62. p62 possesses an N-terminal Phox and Bem1 (PB1) domain that mediates hetero- and homo-oligomerization of p62 (Lamark et al. 2003) and the LC3 recognition sequence (LRS) ⁄LC3 interacting region (LIR) identified in murine (Ichimura et al. 2008) and…”
BackgroundInfluentialThe axonal transport of mitochondria
Saxton, W. M., & Hollenbeck, P. J. (2012) · Journal of Cell Science · doi:10.1242/jcs.053850 · Cited by 1,198 · cited 1× · see citing works
“Indeed, mitochondria are delivered to areas of the axon where metabolic demand is high, such as synapses, active growth cones and branches (Hollenbeck & Saxton 2005).”
BackgroundSeligman, A. M., Karnovsky, M. J., Wasserkrug, H. L., & Hanker, J. S. (1968) · The Journal of Cell Biology · doi:10.1083/jcb.38.1.1 · Cited by 883 · cited 2× · see citing works
“The fixed samples were rinsed with 0.05 M phosphate buffer (pH 7.4) at room temperature and stained for COX activity (Seligman et al. 1968).”
MethodInfluentialStructural Basis for Sorting Mechanism of p62 in Selective Autophagy
Ichimura, Y., Kumanomidou, T., Sou, Y.-S., Mizushima, T., Ezaki, J., Ueno, T., Kominami, E., Yamane, T., Tanaka, K., & Komatsu, M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802182200 · Cited by 803 · cited 9× · see citing works
“…degradation. 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…”
BackgroundMethodInfluentialSelf-citationYang, Y., Gehrke, S., Imai, Y., Huang, Z., Ouyang, Y., Wang, J.-W., Yang, L., Beal, M. F., Vogel, H., & Lu, B. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602493103 · Cited by 798 · cited 1× · see citing works
“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).”
BackgroundThe axonal transport of mitochondria
Hollenbeck, P. J., & Saxton, W. M. (2005) · Journal of Cell Science · doi:10.1242/jcs.02745 · Cited by 771 · see citing works
Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics
Kitamura, T., Koshino, Y., Shibata, F., Oki, T., Nakajima, H., Nosaka, T., & Kumagai, H. (2003) · Experimental Hematology · doi:10.1016/j.exphem.2003.07.005 · Cited by 738 · cited 6× · see citing works
“Retrovirus packaging cells, PLAT-E were provided by Dr T. Kitamura from the University of Tokyo (Kitamura et al. 2003) were transfected with the aforementioned vectors and were cultured at 37 C for 24 h.”
BackgroundMethodInfluential<i>Drosophila</i> Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin
Ziviani, E., Tao, R. N., & Whitworth, A. J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913485107 · Cited by 735 · cited 2× · see citing works
“…which ubiquitylates the outer membrane protein(s) of mitochondria with no membrane potential with the ubiquitylated mitochondria destined for final degradation in part via mitophagy (Narendra et al. 2008, 2010; Geisler et al. 2010; Matsuda et al. 2010; Vives-Bauza et al. 2010; Ziviani et al. 2010).”
BackgroundSekiguchi, M. (1997) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(97)83119-2 · Cited by 668 · see citing works
Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics
Kitamura, T., KOSHINO, Y., Shibata, F., et al. (2003) · Experimental Hematology · doi:10.1016/s0301-472x(03)00260-1 · Cited by 642 · see citing works
What is the role of protein aggregation in neurodegeneration?
Ross, C. A., & Poirier, M. A. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1742 · Cited by 604 · cited 1× · see citing works
“Such inclusion bodies have been suggested to be pathogenic; however, growing lines of evidence indicate that they are not the main cause of toxicity but a consequence of a protective cellular response (Ross & Poirier 2005).”
BackgroundCharacterization and Dynamics of Aggresome Formation by a Cytosolic Gfp-Chimera✪
García‐Mata, R., Bebők, Z., Sorscher, E. J., & Sztul, E. S. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.146.6.1239 · Cited by 597 · cited 2× · see citing works
“…concentrated into proteinacious inclusion bodies and ⁄ or recognized by HDAC6 to be transported along microtubles, organized into a perinuclear aggregation (an aggresome) and sometimes degraded by autophagy (Johnston et al. 1998; Garcia-Mata et al. 1999; Olzmann et al. 2007; Kirkin et al. 2009).”
BackgroundThe Adaptor Protein p62/SQSTM1 Targets Invading Bacteria to the Autophagy Pathway
Zheng, Y. T., Shahnazari, S., Brech, A., Lamark, T., Johansen, T., & Brumell, J. H. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900441 · Cited by 581 · cited 1× · see citing works
“This idea is based on the preceding paper regarding p62-mediated pexophagy and xenophagy i.e., a selective autophagy for cytoplasm-invading bacteria and superfluous peroxisomes (Kim et al. 2008; Yoshikawa et al. 2009; Zheng et al. 2009).”
BackgroundUbiquitin Chain Editing Revealed by Polyubiquitin Linkage-Specific Antibodies
Newton, K., Matsumoto, M. L., Wertz, I. E., Kirkpatrick, D. S., Lill, J. R., Tan, J., Dugger, D. L., Gordon, N. C., Sidhu, S. S., Fellouse, F. A., et al. (2008) · Cell · doi:10.1016/j.cell.2008.07.039 · Cited by 553 · cited 4× · see citing works
“In immunocytochemistry experiments, the Apu3 and HWA4C4 antibodies, which exclusively react with ubiquitin chain linked at K63, clearly stained Parkin-localized mitochondria, whereas Apu2, which specifically recognizes K48-linkage polyubiquitylation, did not stain Parkin-localized mitochondria as well (Fig.”
MethodInfluentialUbiquitin signals autophagic degradation of cytosolic proteins and peroxisomes
Kim, P. K., Hailey, D. W., Mullen, R. T., & Lippincott‐Schwartz, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810611105 · Cited by 533 · cited 2× · see citing works
“This idea is based on the preceding paper regarding p62-mediated pexophagy and xenophagy i.e., a selective autophagy for cytoplasm-invading bacteria and superfluous peroxisomes (Kim et al. 2008; Yoshikawa et al. 2009; Zheng et al. 2009).”
BackgroundLee, J., Nagano, Y., Taylor, J. P., Lim, K. L., & Yao, T. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201001039 · Cited by 517 · cited 1× · see citing works
“After our manuscript had been accepted, Lee et al. (2010) independently published results that are related to those described herein.”
ResultPhysiological significance of selective degradation of p62 by autophagy
Komatsu, M., & Ichimura, Y. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.02.017 · Cited by 516 · cited 1× · see citing works
“…lines of evidence indicate that p62, a selective substrate of autophagy, acts as a shuttle protein that transports ubiquitylated proteins to the autophagosome via interactions with both the ubiquitin and autophagic component LC3 (Kirkin et al. 2009; Komatsu & Ichimura 2010).”
BackgroundSelf-citationListeria monocytogenes ActA-mediated escape from autophagic recognition
Yoshikawa, Y., Ogawa, M., Hain, T., Yoshida, M., Fukumatsu, M., Kim, M., Mimuro, H., Nakagawa, I., Yanagawa, T., Ishii, T., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1967 · Cited by 449 · see citing works
Nakada, K., Inoue, K., Ono, T., Isobe, K., Ogura, A., Goto, Y., Nonaka, I., & Hayashi, J. (2001) · Nature Medicine · doi:10.1038/90976 · Cited by 430 · cited 1× · see citing works
“COX electronmicrographs were carried out as reported previously (Nonaka et al. 1989; Nakada et al. 2001).”
MethodSelf-citationStructural basis of target recognition by Atg8/LC3 during selective autophagy
Noda, N. N., Kumeta, H., Nakatogawa, H., Satoo, K., Adachi, W., Ishii, J., Fujioka, Y., Ohsumi, Y., & Inagaki, F. (2008) · Genes to Cells · doi:10.1111/j.1365-2443.2008.01238.x · Cited by 428 · cited 3× · see citing works
“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.”
BackgroundInteraction Codes within the Family of Mammalian Phox and Bem1p Domain-containing Proteins
Lamark, T., Perander, M., Outzen, H., Kristiansen, K., Øvervatn, A., Michaelsen, E., Bjørkøy, G., & Johansen, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303221200 · Cited by 396 · cited 2× · see citing works
“p62 possesses an N-terminal Phox and Bem1 (PB1) domain that mediates hetero- and homo-oligomerization of p62 (Lamark et al. 2003) and the LC3 recognition sequence (LRS) ⁄LC3 interacting region (LIR) identified in murine (Ichimura et al.”
BackgroundControl of mitochondrial transport and localization in neurons
MacAskill, A. F., & Kittler, J. T. (2009) · Trends in Cell Biology · doi:10.1016/j.tcb.2009.11.002 · Cited by 372 · cited 1× · see citing works
“In axons, microtubules are oriented with their plus ends toward the periphery, and damaged mitochondria are subjected to retrograde transport along microtubules toward the cell body, which is the same direction of aggresome formation (MacAskill & Kittler 2010).”
BackgroundOlzmann, J. A., Li, L., Chudaev, M. V., Chen, J., Perez, F. A., Palmiter, R. D., & Chin, L. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200611128 · Cited by 335 · cited 2× · see citing works
“…concentrated into proteinacious inclusion bodies and ⁄ or recognized by HDAC6 to be transported along microtubles, organized into a perinuclear aggregation (an aggresome) and sometimes degraded by autophagy (Johnston et al. 1998; Garcia-Mata et al. 1999; Olzmann et al. 2007; Kirkin et al. 2009).”
BackgroundBedford, L., Hay, D., Devoy, A., Paine, S., Powe, D. G., Seth, R., Gray, T., Topham, I., Fone, K., Rezvani, N., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.2218-08.2008 · Cited by 327 · cited 2× · see citing works
“(2000) showed that many mitochondria are concentrated in the early forms of Lewy bodies and Bedford et al. (2008) also demonstrated deposits of mitochondria in the early form of the Lewy body (pale body) in patients with Parkinson’s disease.”
BackgroundGai, W. P., Yuan, H. X., Li, X. Q., Power, J. T. H., Blumbergs, P. C., & Jensen, P. H. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7527 · Cited by 272 · cited 1× · see citing works
“Interestingly, electron microscopic analysis by Gai et al. (2000) showed that many mitochondria are concentrated in the early forms of Lewy bodies and Bedford et al. (2008) also demonstrated deposits of mitochondria in the early form of the Lewy body (pale body) in patients with Parkinson’s disease.”
BackgroundControlled Synthesis of Polyubiquitin Chains
Pickart, C. M., & Raasi, S. (2005) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(05)99002-2 · Cited by 266 · cited 2× · see citing works
“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).”
BackgroundLysine 63‐linked polyubiquitin chain may serve as a targeting signal for the 26S proteasome
Saeki, Y., Kudo, T., Sone, T., Kikuchi, Y., Yokosawa, H., Toh‐e, A., & Tanaka, K. (2009) · The EMBO Journal · doi:10.1038/emboj.2008.305 · Cited by 260 · cited 1× · see citing works
“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).”
BackgroundSelf-citationAlterations in the common fragile site gene Parkin in ovarian and other cancers
Denison, S. R., Wang, F., Becker, N. A., Schüle, B., Kock, N., Phillips, L. A., Klein, C., & Smith, D. I. (2003) · Oncogene · doi:10.1038/sj.onc.1207072 · Cited by 224 · cited 1× · see citing works
“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.”
BackgroundHampe, C., Ardila-Osorio, H., Fournier, M., Brice, A., & Corti, O. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl131 · Cited by 222 · cited 2× · see citing works
“…(i.e., the MBP moiety of the MBP-fused Parkin in vitro and the GFP moiety of the GFP-Parkin in cell) was intact in these Parkin mutations (Hampe et al. 2006; Matsuda et al. Genes to Cells (2010) 15, 887–900 2010 The Authors Journal compilation 2010 by the Molecular Biology Society of…”
BackgroundDiverse Effects of Pathogenic Mutations of Parkin That Catalyze Multiple Monoubiquitylation in Vitro
Matsuda, N., Kitami, T., Suzuki, T., Mizuno, Y., Hattori, N., & Tanaka, K. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m510393200 · Cited by 180 · cited 1× · see citing works
“Furthermore, mutations in the RING2 catalytic domain (T415N and G430D), which abolished the E3 activity of Parkin in vitro (Hampe et al. 2006; Matsuda et al. 2006), impeded the mitochondrial clustering (Fig.”
BackgroundSelf-citationThe N-terminus and Phe52 residue of LC3 recruit p62/SQSTM1 into autophagosomes
Shvets, E., Fass, E., Scherz‐Shouval, R., & Elazar, Z. (2008) · Journal of Cell Science · doi:10.1242/jcs.026005 · Cited by 159 · cited 3× · see citing works
“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.”
BackgroundMatsuda, N., & Tanaka, K. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1231 · Cited by 87 · cited 1× · see citing works
“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).”
BackgroundSelf-citationUbiquitin–proteasome system dysfunction in Parkinson’s disease: current evidence and controversies
Lim, K. (2007) · Expert Review of Proteomics · doi:10.1586/14789450.4.6.769 · Cited by 72 · cited 1× · see citing works
“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).”
BackgroundWang, H., Matsuzawa, A., Brown, S. A., Zhou, J., Guy, C. S., Tseng, P., Forbes, K., Nicholson, T. P., Sheppard, P. W., Häcker, H., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810461105 · Cited by 67 · cited 4× · see citing works
“In immunocytochemistry experiments, the Apu3 and HWA4C4 antibodies, which exclusively react with ubiquitin chain linked at K63, clearly stained Parkin-localized mitochondria, whereas Apu2, which specifically recognizes K48-linkage polyubiquitylation, did not stain Parkin-localized mitochondria as well (Fig.”
MethodInfluentialTissue specificity in cytochrome c oxidase deficient myopathy
Nonaka, I., Koga, Y., Ohtaki, E., & Yamamoto, M. (1989) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(89)90136-6 · Cited by 33 · cited 1× · see citing works
“COX electronmicrographs were carried out as reported previously (Nonaka et al. 1989; Nakada et al. 2001).”
Method
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Sorted by citations
Autophagy: Renovation of Cells and Tissues
Mizushima, N., & Komatsu, M. (2011) · Cell · doi:10.1016/j.cell.2011.10.026 · Cited by 6,467 · see citing works
“occurs normally in p62-deficient cells (Narendra et al., 2010b; Okatsu et al., 2010).”
BackgroundSelf-citationGuidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
Self-citationGuidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996 · see citing works
Self-citationYoule, R. J., & Narendra, D. P. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3028 · Cited by 3,273 · see citing works
The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy
Lazarou, M., Sliter, D. A., Kane, L. A., Sarraf, S. A., Wang, C., Burman, J. L., Sideris, D. P., Fogel, A. I., & Youle, R. J. (2015) · Nature · doi:10.1038/nature14893 · Cited by 2,774 · see citing works
Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
Self-citationThe Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease
Pickrell, A. M., & Youle, R. J. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.007 · Cited by 2,310 · see citing works
“Although an initial report indicated that p62 is required for Parkin-mediated mitophagy (Geisler et al., 2010a), two groups using p62-KOmouse embryonic fibroblasts did not find that it is essential for mitophagy (Narendra et al., 2010a; Okatsu et al., 2010).”
BackgroundSwatek, K. N., & Komander, D. (2016) · Cell Research · doi:10.1038/cr.2016.39 · Cited by 2,070 · see citing works
Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance
Pickles, S., Vigié, P., & Youle, R. J. (2018) · Current Biology · doi:10.1016/j.cub.2018.01.004 · Cited by 2,081 · see citing works
Selective autophagy mediated by autophagic adapter proteins
Johansen, T., & Lamark, T. (2011) · Autophagy · doi:10.4161/auto.7.3.14487 · Cited by 1,730 · see citing works
NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria
Zhong, Z., Umemura, A., Sanchez-Lopez, E., Liang, S., Shalapour, S., Wong, J., He, F., Boassa, D., Perkins, G., Ali, S. R., et al. (2016) · Cell · doi:10.1016/j.cell.2015.12.057 · Cited by 1,197 · see citing works
Chu, C. T., Ji, J., Dagda, R. K., Jiang, J. F., Tyurina, Y. Y., Kapralov, A. A., Tyurin, V. A., Yanamala, N., Shrivastava, I. H., Mohammadyani, D., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2837 · Cited by 1,083 · see citing works
Mitophagy: mechanisms, pathophysiological roles, and analysis
Ding, W.-X., & Yin, X.-M. (2012) · bchm · doi:10.1515/hsz-2012-0119 · Cited by 1,032 · see citing works
“SMURF1 In a recent high-content, genome-wide small interfering RNA screen to detect genes required for the colocalization of Sindbis virus capsid protein with autophagolysosomes, Orvedahl et al. (2011) identifi ed 141 candidate genes required for viral autophagy.”
BackgroundBroad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy
Chan, N. C., Salazar, A. M., Pham, A. H., Sweredoski, M. J., Kolawa, N. J., Graham, R. L. J., Hess, S., & Chan, D. C. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr048 · Cited by 993 · see citing works
“However, p62 appears to be involved in controlling mitochondrial distribution and is not essential for degradation of mitochondria (17,18).”
BackgroundResultInfluentialMitochondrial dynamics and mitochondrial quality control
Ni, H.-M., Williams, J. A., & Ding, W.-X. (2015) · Redox Biology · doi:10.1016/j.redox.2014.11.006 · Cited by 931 · see citing works
“In addition, Parkin also recruits Ambra1 (a Beclin-1 interacting protein) to depolarized mitochondria to initiate engulfment of damaged mitochondria by autophagosomes [68].”
BackgroundWong, Y. C., & Holzbaur, E. L. F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1405752111 · Cited by 812 · see citing works
“These results further support a role for p62 as a regulator of mitochondrial aggregation and clustering during parkin-dependent mitophagy (25, 26).”
BackgroundMethodResultInfluentialNarendra, D. P., Kane, L. A., Hauser, D. N., Fearnley, I. M., & Youle, R. J. (2010) · Autophagy · doi:10.4161/auto.6.8.13426 · Cited by 789 · see citing works
p62/ SQSTM 1 functions as a signaling hub and an autophagy adaptor
Katsuragi, Y., Ichimura, Y., & Komatsu, M. (2015) · FEBS Journal · doi:10.1111/febs.13540 · Cited by 795 · see citing works
Self-citationMitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment
Greene, A. W., Grenier, K., Aguileta, M. A., Muise, S., Farazifard, R., Haque, M. E., McBride, H. M., Park, D. S., & Fon, E. A. (2012) · The EMBO Reports · doi:10.1038/embor.2012.14 · Cited by 711 · see citing works
“In contrast, CCCP induced larger perinuclear GFPParkin-positive mitochondrial clusters, as reported previously [22].”
ResultExner, N., Lutz, A. K., Haass, C., & Winklhofer, K. F. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.170 · Cited by 652 · see citing works
PINK1- and Parkin-mediated mitophagy at a glance
Jin, S. M., & Youle, R. J. (2012) · Journal of Cell Science · doi:10.1242/jcs.093849 · Cited by 631 · see citing works
Yoshii, S. R., Kishi, C., Ishihara, N., & Mizushima, N. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.209338 · Cited by 612 · see citing works
Okatsu, K., Oka, T., Iguchi, M., Imamura, K., Kosako, H., Tani, N., Kimura, M., Go, E., Koyano, F., Funayama, M., et al. (2012) · Nature Communications · doi:10.1038/ncomms2016 · Cited by 602 · see citing works
Self-citationShiba-Fukushima, K., Imai, Y., Yoshida, S., Ishihama, Y., Kanao, T., Sato, S., & Hattori, N. (2012) · Scientific Reports · doi:10.1038/srep01002 · Cited by 577 · see citing works
Self-citationCleaning house: selective autophagy of organelles
Anding, A. L., & Baehrecke, E. H. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.02.016 · Cited by 576 · see citing works
“Whether p62/SQSTM1 is necessary for the PINK1/Parkin mitophagy pathway is inconclusive, as the data are conflicting (Geisler et al., 2010; Lazarou et al., 2015; Narendra et al., 2010b; Okatsu et al., 2010).”
BackgroundMitochondria: The Next (Neurode)Generation
Schon, E. A., & Przedborski, S. (2011) · Neuron · doi:10.1016/j.neuron.2011.06.003 · Cited by 568 · see citing works
Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness
Katajisto, P., Döhla, J., Chaffer, C. L., Pentinmikko, N., Marjanovic, N. D., Iqbal, S., Zoncu, R., Chen, W. W., Weinberg, R. A., & Sabatini, D. M. (2015) · Science · doi:10.1126/science.1260384 · Cited by 542 · see citing works
“Mitochondria that have lower membrane potential (ΔΨm)–an index of mitochondrial function– localize perinuclearly (18), and high ΔΨm is linked to stem-like traits (19, 20).”
BackgroundThe role of PINK1–Parkin in mitochondrial quality control
Narendra, D. P., & Youle, R. J. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01513-9 · Cited by 580 · see citing works
“Two other ubiquitin-binding adaptors, the paralogues p62 (also known as SQSTM1) and NBR1, are also recruited but cannot induce mitophagy in the absence of the other autophagy adaptors 52,53 .”
Aggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy
Lamark, T., & Johansen, T. (2012) · International Journal of Cell Biology · doi:10.1155/2012/736905 · Cited by 490 · see citing works
“For instance, p62 is involved in clustering of mitochondria during mitophagy [237, 238].”
BackgroundIntegration of cellular bioenergetics with mitochondrial quality control and autophagy
Hill, B. G., Benavides, G. A., Lancaster, J. R., Ballinger, S. W., Dell’Italia, L., Zhang, J., & Darley-Usmar, V. M. (2012) · Biological Chemistry · doi:10.1515/hsz-2012-0198 · Cited by 481 · see citing works
“…p62 may then be involved in recruiting the mitochondrial cargo into autophagosomes (Pankiv et al., 2007 ; Ding et al. , 2010 ; Geisler et al. , 2010 ), although contradictory reports exist concerning whether p62 is indeed essential for mitophagy (Narendra et al. , 2010a ; Okatsu et al. , 2010 ).”
Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System
Kocatürk, N. M., & Gözüaçık, D. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00128 · Cited by 415 · see citing works
“On the other hand, the autophagy receptor p62 was essential for clustering of damaged mitochondria in perinuclear region of the cells, but not for mitophagy (Narendra et al., 2010; Okatsu et al., 2010).”
BackgroundThe three ‘P’s of mitophagy: PARKIN.; PINK1.; and post-translational modifications
Durcan, T. M., & Fon, E. A. (2015) · Genes & Development · doi:10.1101/gad.262758.115 · Cited by 400 · see citing works
“…receptors such as p62, optineurin, and NBR1 (Geisler et al. 2010; Narendra et al. 2010a; Chan et al. 2011;Wong andHolzbaur 2014), which in turn elicits the targeting of the damaged mitochondria to LC3-positive phagophores for clearance in the lysosome (Narendra et al. 2010a; Okatsu et al. 2010).”
BackgroundAMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1
Strappazzon, F., Nazio, F., Corrado, M., Cianfanelli, V, Romagnoli, A., Fimia, G. M., Campello, S., Nardacci, R., Piacentini, M., Campanella, M., et al. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.139 · Cited by 399 · see citing works
Hamacher‐Brady, A., & Brady, N. R. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2087-8 · Cited by 396 · see citing works
“Mechanistically, p62 has a role in clustering mitochondria during mitophagy [55, 81, 82], and has been reported to be required [79], or dispensable in downstream mitochondrial degradation [55, 81].”
BackgroundUSP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin
Durcan, T. M., Tang, M. Y., Pérusse, J. R., Dashti, E. A., Aguileta, M. A., McLelland, G., Gros, P., Shaler, T. A., Faubert, D., Coulombe, B., et al. (2014) · The EMBO Journal · doi:10.15252/embj.201489729 · Cited by 375 · see citing works
Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases
Riley, B. E., Lougheed, J. C., Callaway, K., Velasquez, M., Brecht, E., Nguyen, L., Shaler, T. A., Walker, D., Yang, Y., Regnström, K. J., et al. (2013) · Nature Communications · doi:10.1038/ncomms2982 · Cited by 368 · see citing works
Targeting Mitochondrial Dysfunction: Role for PINK1 and Parkin in Mitochondrial Quality Control
Narendra, D. P., & Youle, R. J. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3799 · Cited by 367 · see citing works
“At least in mouse embryonic fibroblasts lacking VDAC1 or p62, VDAC1 (49) and p62 (28, 32) appear to be dispensible for Parkin-induced mitophagy, although p62 appears to be required for mitochondrial clustering (28, 32).”
BackgroundNBR1 acts as an autophagy receptor for peroxisomes
Deosaran, E., Larsen, K. B., Hua, R., Sargent, G., Wang, Y., Kim, S., Lamark, T., Jauregui, M., Law, K. B., Lippincott‐Schwartz, J., et al. (2012) · Journal of Cell Science · doi:10.1242/jcs.114819 · Cited by 359 · see citing works
“…in mitophagy (the autophagic degradation of mitochondria); however, it is not clear whether p62 is required for targeting of ubiquitylated mitochondria to autophagosomes or serves a different functional role (Ding et al., 2010; Geisler et al., 2010; Narendra et al., 2010; Okatsu et al., 2010).”
BackgroundPreconditioning Involves Selective Mitophagy Mediated by Parkin and p62/SQSTM1
Huang, C., Andres, A. M., Ratliff, E. P., Hernandez, G., Lee, P. P. W., & Gottlieb, R. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020975 · Cited by 344 · see citing works
Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to ParkinsonismPreprint
Narendra, D. P., Walker, J. E., & Youle, R. J. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a011338 · Cited by 341 · see citing works
“…potential is restored (Tanaka et al. 2010); (2) the spherical mitochondria form clumps that resemble bunches of grapes (Narendra et al. 2010a; Okatsu et al. 2010); (3) the clumps of mitochondria are gathered in a perinuclear localization possibly because of increased minus end transport…”
BackgroundInfluentialThe deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy
Cornelissen, T., Haddad, D., Wauters, F., Humbeeck, C. V., Mandemakers, W. J., Koentjoro, B., Sue, C. M., Gevaert, K., Strooper, B. D., Verstreken, P., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu244 · Cited by 337 · see citing works
Pathogenesis of Parkinson's disease
Hirsch, E. C., Jenner, P., & Przedborski, S. (2013) · Movement Disorders · doi:10.1002/mds.25032 · Cited by 336 · see citing works
Matsumoto, G., Shimogori, T., Hattori, N., & Nukina, N. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv179 · Cited by 317 · see citing works
“It is controversial whether p62 is required for mitophagy (26,37,44,45).”
BackgroundSelf-citationMolecular Mechanisms of Mitochondrial Autophagy/Mitophagy in the Heart
Saito, T., & Sadoshima, J. (2015) · Circulation Research · doi:10.1161/circresaha.116.303790 · Cited by 321 · see citing works
“However, whether p62 is essential for Parkin-mediated mitochondrial autophagy is controversial.(59,82,83) Although degradation of the IMM and matrix proteins occurs through mitochondrial autophagy, degradation of OMM proteins can take place also through a proteasomedependent mechanism mediated by Parkin.”
Yun, J., Puri, R., Yang, H. M., Lizzio, M. A., Wu, C., Sheng, Z., & Guo, M. (2014) · eLife · doi:10.7554/elife.01958 · Cited by 325 · see citing works
“This leads to recruitment of Parkin to the depolarized mitochondria, ultimately resulting in autophagic degradation of these mitochondria (Narendra et al., 2008; Ding et al., 2010; Gegg et al., 2010; Geisler et al., 2010; Matsuda et al., 2010; Narendra et al., 2010; Okatsu et al., 2010; Tanaka et al., 2010; Vives-Bauz…”
BackgroundParkin-Independent Mitophagy Controls Chemotherapeutic Response in Cancer Cells
Villa, E., Proïcs, E., Rubio‐Patiño, C., Obba, S., Zunino, B., Bossowski, J. P., Rozier, R., Chiche, J., Mondragón, L., Riley, J. S., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.087 · Cited by 315 · see citing works
“While p62 was initially shown to be critical for removing depolarized mitochondria by transporting them to autophagosomes, later studies suggested a possible redundancy with the related Ub- and Atg8/LC3II-binding protein NBR1 (Narendra et al., 2010; Okatsu et al., 2010), NDP52 (nuclear domain 10 protein 52, also known…”
Backgroundp62/SQSTM1/A170: Physiology and pathology
Komatsu, M., Kageyama, S., & Ichimura, Y. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.07.004 · Cited by 301 · see citing works
Self-citationChang, Y., Yan, W., He, X., Zhang, L., Li, C., Huang, H., Nace, G., Geller, D. A., Lin, J., & Tsung, A. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.04.009 · Cited by 288 · see citing works
Itakura, E., Kishi-Itakura, C., Koyama-Honda, I., & Mizushima, N. (2012) · Journal of Cell Science · doi:10.1242/jcs.094110 · Cited by 286 · see citing works
“This model, however, is also controversial; recent reports have suggested that p62 is not essential for mitochondrial recognition by the autophagosome, but rather is important for perinuclear clustering of depolarized mitochondria (Narendra et al., 2010b; Okatsu et al., 2010).”
ResultKim, M., Bae, S. H., Ryu, J., Kwon, Y., Oh, J.-H., Kwon, J., Moon, J., Kim, K., Miyawaki, A., Lee, M. G., et al. (2016) · Autophagy · doi:10.1080/15548627.2016.1183081 · Cited by 286 · see citing works
Parkin Interacts with Ambra1 to Induce Mitophagy
Van Humbeeck, C., Cornelissen, T., Hofkens, H., Mandemakers, W., Gevaert, K., De Strooper, B., & Vandenberghe, W. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1917-11.2011 · Cited by 287 · see citing works
Parkin and mitophagy in cancer
Bernardini, J. P., Lazarou, M., & Dewson, G. (2016) · Oncogene · doi:10.1038/onc.2016.302 · Cited by 282 · see citing works
p62/SQSTM1 – steering the cell through health and disease
Sánchez‐Martín, P., & Komatsu, M. (2018) · Journal of Cell Science · doi:10.1242/jcs.222836 · Cited by 280 · see citing works
“whereas others proposed that it is only required for mitochondrial clustering (Narendra et al., 2010; Okatsu et al., 2010).”
BackgroundSelf-citationRole and Mechanisms of Mitophagy in Liver Diseases
Ma, X., McKeen, T., Zhang, J., & Ding, W. (2020) · Cells · doi:10.3390/cells9040837 · Cited by 279 · see citing works
Spatiotemporally controlled induction of autophagy-mediated lysosome turnover
Hung, Y.-H., Chen, L. M.-W., Yang, J., & Yang, W. Y. (2013) · Nature Communications · doi:10.1038/ncomms3111 · Cited by 270 · see citing works
Ivankovic, D., Chau, K., Schapira, A. H. V., & Gegg, M. E. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13412 · Cited by 264 · see citing works
Phosphorylated ubiquitin chain is the genuine Parkin receptor
Okatsu, K., Koyano, F., Kimura, M., Kosako, H., Saeki, Y., Tanaka, K., & Matsuda, N. (2015) · The Journal of Cell Biology · doi:10.1083/jcb.201410050 · Cited by 261 · see citing works
“A mitochondrial localized ubiquitin chain recruits Parkin to energized mitochondria Previous assays using linkage-specific anti-polyubiquitin chain antibodies (Okatsu et al., 2010), a linkage-specific ubiquitin chain binding probe (van Wijk et al.”
BackgroundInfluentialSelf-citationWei, H., Liu, L., & Chen, Q. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.03.013 · Cited by 256 · see citing works
“elimination of damaged mitochondria, challenging the role of this adaptor in the Pink1/Parkin pathway [53-55].”
BackgroundMitochondrial morphology in mitophagy and macroautophagy
Gomes, L. C., & Scorrano, L. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.02.012 · Cited by 250 · see citing works
“After ubiquitination and recruitment of p62, depolarized mitochondria are transported along microtubules to the perinuclear region, where they form “mito-aggresome” structures [66,68,70].”
BackgroundDecision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination
Ham, S. J., Lee, D. S., Yoo, H., Jun, K., Shin, H., & Chung, J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1909814117 · Cited by 251 · see citing works
“The Parkin T415N mutation has been reported to have no defect in translocation to the mitochondria, but the ability of ubiquitinating substrates is reduced (46, 47).”
BackgroundMitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy?
Higgins, G. C., & Coughlan, M. T. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12503 · Cited by 251 · see citing works
“, 2010), p62 has also been reported to be dispensable (Okatsu et al., 2010; Narendra et al., 2010a).”
BackgroundInfluentialMitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells
Liu, K., Lee, J., Kim, J. Y., Wang, L., Tian, Y., Chan, S. T., Cho, C., Machida, K., Chen, D., & Ou, J. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.09.022 · Cited by 246 · see citing works
p62: a versatile multitasker takes on cancer
Moscat, J., & Díaz-Meco, M. T. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.02.008 · Cited by 239 · see citing works
“Unfortunately, however, data from p62 knockout cells do not seem to support such a role for p62 [44,45].”
BackgroundThe ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation
Yamano, K., Matsuda, N., & Tanaka, K. (2016) · EMBO Reports · doi:10.15252/embr.201541486 · Cited by 239 · see citing works
“However, p62-KO cells can still degrade the damaged mitochondria through the autophagy machinery, raising the possibility that binding between p62 and LC3 is not sufficient for mitophagy [129,130].”
Self-citationAutophagy Receptors and Neurodegenerative Diseases
Deng, Z., Purtell, K., Lachance, V., Wold, M. S., Chen, S., & Yue, Z. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.01.001 · Cited by 239 · see citing works
“Some studies in mammalian cell lines show that knockdown of p62 does not impair mitophagy and instead point to a role for p62 in the aggregation of damaged mitochondria [43,82,83].”
BackgroundDoblado, L., Lueck, C., Rey, C., Samhan-Arias, A. K., Priéto, I., Stacchiotti, A., & Monsalve, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083903 · Cited by 229 · see citing works
“In this context, the forced overexpression of p62 levels results in better mitochondrial function, an improvement in mitophagy, and the maintenance of mitochondrial homeostasis [9,245].”
BackgroundEvolving and Expanding the Roles of Mitophagy as a Homeostatic and Pathogenic Process
Gustafsson, Å. B., & Dorn, G. W. (2018) · Physiological Reviews · doi:10.1152/physrev.00005.2018 · Cited by 229 · see citing works
Hollville, É., Carroll, R. G., Cullen, S. P., & Martin, S. J. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.06.001 · Cited by 221 · see citing works
A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance
Hammerling, B. C., Najor, R. H., Cortez, M. Q., Shires, S. E., Leon, L. J., Gonzalez, E. R., Boassa, D., Phan, S., Thor, A., Jimenez, R. E., et al. (2017) · Nature Communications · doi:10.1038/ncomms14050 · Cited by 216 · see citing works
Deubiquitinating enzymes regulate PARK2-mediated mitophagy
Wang, Y., Serricchio, M., Jauregui, M., Shanbhag, R., Stoltz, T., Paolo, C. T. D., Kim, P. K., & McQuibban, G. A. (2015) · Autophagy · doi:10.1080/15548627.2015.1034408 · Cited by 220 · see citing works
Organellophagy: Eliminating cellular building blocks via selective autophagy
Okamoto, K. (2014) · The Journal of Cell Biology · doi:10.1083/jcb.201402054 · Cited by 218 · see citing works
Versatile Roles of K63-Linked Ubiquitin Chains in Trafficking
Erpapazoglou, Z., Walker, O., & Haguenauer‐Tsapis, R. (2014) · Cells · doi:10.3390/cells3041027 · Cited by 203 · see citing works
“HDAC6 was shown to specifically interact with the UbK63 polyubiquitylated mutant isoform of DJ-1, a protein that is involved in familial Parkinson’s Disease.”
BackgroundInfluentialMechanisms and roles of mitophagy in neurodegenerative diseases
Wang, Y., Liu, N., & Lu, B. (2019) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13140 · Cited by 214 · see citing works
TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control
Gatliff, J., East, D., Crosby, J., Abeti, R., Harvey, R., Craigen, W., Parker, P., & Campanella, M. (2014) · Autophagy · doi:10.4161/15548627.2014.991665 · Cited by 215 · see citing works
“Having demonstrated the differences in SQSTM1 relocation to mitochondria according to TSPO expression we next explored the translocation of the E3 ubiquitin ligase PARK2, which is pivotal for the recruitment of SQSTM1 by polyubiquitinating OMM proteins.(53) The translocation of PARK2 was assessed by transfecting cells…”
MethodMitophagy: A Complex Mechanism of Mitochondrial Removal
Novak, I. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4407 · Cited by 210 · see citing works
“Whereas p62 recruitment is shown to be necessary for PINK1/Parkin-induced mitophagy (31), the mitophagy can occur even in the absence of p62 at the mitochondria (28).”
Parkin-catalyzed Ubiquitin-Ester Transfer Is Triggered by PINK1-dependent Phosphorylation
Iguchi, M., Kujuro, Y., Okatsu, K., Koyano, F., Kosako, H., Kimura, M., Suzuki, N., Uchiyama, S., Tanaka, K., & Matsuda, N. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.467530 · Cited by 209 · see citing works
“Plasmids for expressing WT or various PINK1 and Parkin mutants have been described previously (6, 10, 11, 42) or were newly constructed by conventional methods.”
BackgroundMethodSelf-citationIron-starvation-induced mitophagy mediates lifespan extension upon mitochondrial stress in C.elegans
Schiavi, A., Maglioni, S., Palikaras, K., Shaik, A., Strappazzon, F., Brinkmann, V., Torgovnick, A., Castelein, N., De Henau, S., Braeckman, B. P., et al. (2015) · Current Biology · doi:10.1016/j.cub.2015.05.059 · Cited by 209 · see citing works
Autophagy and mitophagy in diabetic cardiomyopathy
Kobayashi, S., & Liang, Q. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.05.020 · Cited by 203 · see citing works
Cemma, M., Kim, P. K., & Brumell, J. H. (2011) · Autophagy · doi:10.4161/auto.7.3.14046 · Cited by 203 · see citing works
Hepatitis C Virus Induces the Mitochondrial Translocation of Parkin and Subsequent Mitophagy
Kim, S., Syed, G. H., & Siddiqui, A. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003285 · Cited by 201 · see citing works
Mitochondrial proteostasis in the context of cellular and organismal health and aging
Moehle, E. A., Shen, K., & Dillin, A. G. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.tm117.000893 · Cited by 193 · see citing works
Phosphorylation of Mitochondrial Polyubiquitin by PINK1 Promotes Parkin Mitochondrial Tethering
Shiba‐Fukushima, K., Arano, T., Matsumoto, G., Inoshita, T., Yoshida, S., Ishihama, Y., Ryu, K., Nukina, N., Hattori, N., & Imai, Y. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004861 · Cited by 186 · see citing works
Self-citationMechanisms of mitochondria and autophagy crosstalk
Rambold, A. S., & Lippincott‐Schwartz, J. (2011) · Cell Cycle · doi:10.4161/cc.10.23.18384 · Cited by 191 · see citing works
The interplay between autophagy and ROS in tumorigenesis
Kongara, S., & Karantza, V. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00171 · Cited by 182 · see citing works
“On the other hand, p62−/− MEFs do not have a defect in mitochondrial clearance upon CCCP treatment, despite the finding that p62 causes perinuclear, and thus autophagosome-like, mitochondrial clustering (Okatsu et al., 2010; Narendra et al., 2010b).”
BackgroundAutophagic and endo-lysosomal dysfunction in neurodegenerative disease
Malik, B. R., Maddison, D. C., Smith, G. A., & Peters, O. M. (2019) · Molecular Brain · doi:10.1186/s13041-019-0504-x · Cited by 180 · see citing works
“Though responsible for recruiting LC3-II to the poly-ubiquitinated MOM [135], p62 is dispensable [134, 136] but can improve the efficiency of mitochondrial incorporation into autophagosomes at a later stage in the process.”
BackgroundBNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects
Choi, G. E., Lee, H. J., Chae, C. W., Cho, J. H., Jung, Y. H., Kim, J. S., Kim, S. Y., Lim, J. R., & Han, H. J. (2021) · Nature Communications · doi:10.1038/s41467-020-20679-y · Cited by 182 · see citing works
The genetic architecture of mitochondrial dysfunction in Parkinson’s disease
Larsen, S. B., Hanss, Z., & Krüger, R. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2768-8 · Cited by 181 · see citing works
“This accumulation of ubiquitinated proteins triggers the recruitment of p62 on the mitochondrial surface (Okatsu et al. 2010). p62 in turn triggers the engulfment of damaged mitochondria in the autophagosome that will lead to its degradation by the autophagy pathway (Okatsu et al. 2010).”
BackgroundThe Function of Autophagy in Neurodegenerative Diseases
Kiriyama, Y., & Nochi, H. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161125990 · Cited by 168 · see citing works
p62/ SQSTM1 and Selective Autophagy in Cardiometabolic Diseases
Jeong, S., Zhang, X., Rodríguez-Vélez, A., Evans, T. D., & Razani, B. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7649 · Cited by 167 · see citing works
“…of mitochondria by ubiquitination, a large body of evidence has implicated p62 as an essential chaperone mediating Parkin-dependent mitophagy (26, 79, 112). p62 can bind the polyubiquitin chains of MOM through its UBA domain and by interacting with Atg8/LC3 on autop-hagosome through its LIR…”
Autophagy in Protein and Organelle TurnoverPreprint
Mizushima, N. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.011023 · Cited by 165 · see citing works
“However, the role of p62 remains controversial; p62 seems to be essential for mitochondrial clustering at the perinuclear region rather than for mitophagy itself (Narendra et al. 2010b; Okatsu et al. 2010).”
BackgroundFunctional interplay between Parkin and Drp1 in mitochondrial fission and clearance
Buhlman, L. M., Damiano, M. G., Bertolin, G., Ferrando-Miguel, R., Lombès, A., Brice, A., & Corti, O. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.05.012 · Cited by 165 · see citing works
Autophagy in Cell Life and Cell Death
Anding, A. L., & Baehrecke, E. H. (2015) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2015.07.012 · Cited by 161 · see citing works
“Whether ubiquitin/ Atg8-binding adaptors such as p62 and NBR1 are necessary for the PINK1/Parkin mitophagy pathway is inconclusive, as the data are conflicting (Geisler et al., 2010; Narendra, Kane, Hauser, Fearnley, & Youle, 2010; Okatsu et al., 2010; Wong & Holzbaur, 2014).”
BackgroundMethodNIPSNAP1 and NIPSNAP2 Act as “Eat Me” Signals for Mitophagy
Abudu, Y. P., Pankiv, S., Mathai, B. J., Lystad, A. H., Bindesbøll, C., Brenne, H. B., Ng, M. Y. W., Thiede, B., Yamamoto, A., Nthiga, T. M., et al. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.03.013 · Cited by 160 · see citing works
Mitophagy: the latest problem for Parkinson's disease
Vives-Bauzá, C., & Przedborski, S. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.11.002 · Cited by 156 · see citing works
Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain
Sarraf, S. A., Shah, H. V., Kanfer, G., Pickrell, A. M., Holtzclaw, L. A., Ward, M. E., & Youle, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.10.041 · Cited by 143 · see citing works
“Because p62 is generally required for aggregate formation, our data suggest that p62 most likely acts upstream of autophagic clearance, similar to its proposed role in mitophagy (Narendra et al., 2010; Okatsu et al., 2010).”
BackgroundFunctional and morphological impact of ER stress on mitochondria
Vannuvel, K., Renard, P., Raes, M. J., & Arnould, T. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24360 · Cited by 155 · see citing works
“The accumulation of ubiquitin-modifications leads to the recruitment of p62 triggering the subsequent activation of the autophagosomal degradation of damaged mitochondria (Okatsu et al., 2010).”
BackgroundEmerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease
Salminen, A., Kaarniranta, K., Haapasalo, A., Hiltunen, M., Soininen, H., & Alafuzoff, I. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.11.005 · Cited by 153 · see citing works
Autophagy: More Than a Nonselective Pathway
Reggiori, F., Komatsu, M., Finley, K. D., & Simonsen, A. (2012) · International Journal of Cell Biology · doi:10.1155/2012/219625 · Cited by 152 · see citing works
“Although p62 has been implicated in the recognition of ubiquitinated mitochondria, elimination of the mitochondria occurs normally in p62-deficient cells [182, 183].”
BackgroundSelf-citationImpaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex
Ebrahimi-Fakhari, D., Saffari, A., Wahlster, L., Di Nardo, A., Turner, D., Lewis, T. L., Conrad, C., Rothberg, J. M., Lipton, J. O., Kölker, S., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.054 · Cited by 146 · see citing works
Li, W., Zhang, X., Zhuang, H., Chen, H.-G., Chen, Y., Tian, W., Wu, W., Li, Y., Wang, S., Zhang, L., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.537050 · Cited by 145 · see citing works
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › 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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