S-nitrosylation regulates mitochondrial quality control via activation of parkin

Ozawa, Kentaro; Komatsubara, Akira T.; Nishimura, Yuhei; Sawada, Tomoyo; Kawafune, Hiroto; Tsumoto, Hiroki; Tsuji, Yuichi; Zhao, Jingquan; Kyotani, Yoji; Tanaka, Toshio; Takahashi, Ryōsuke; Yoshizumi, Masanori

doi:10.1038/srep02202

Cited by 83 publications

(65 citation statements)

References 27 publications

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“…In line with those data, our results showed that extracellular ASN, through activation of nitrosative stress, induces parkin S-nitrosylation and activation leading to decrease in parkin protein level. This is in agreement with previous study by Ozawa et al [57], showing that endogenous S-nitrosylation of parkin is responsible for activation of its E3 ligase activity. Conversely, Dawson's group claimed that S-nitrosylation of parkin is responsible for its inhibition [9], whereas Yao et al [10] showed that NO-mediated posttranslational modifications initially lead to a dramatic increase in parkin activity followed by a decrease in the E3 ligase-ubiquitin-proteasome degradative pathway.…”

Section: Discussionsupporting

confidence: 83%

“…These differences between our data and the results obtained by others might depend on the duration of NO release in cells. In previous papers, different NO donors or complex I inhibitors as well as the mitochondrial-uncoupling reagents induced fast increase, followed by significant decrease in NO liberation [57]. This resulted in parkin S-nitrosylation up to 3 h of treatment followed by denitrosylation at time points when the NO level was no longer increased.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

et al. 2018

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α-Synuclein (ASN) and parkin, a multifunctional E3 ubiquitin ligase, are two proteins that are associated with the pathophysiology of Parkinson's disease (PD). Excessive release of ASN, its oligomerization, aggregation, and deposition in the cytoplasm contribute to neuronal injury and cell death through oxidative-nitrosative stress induction, mitochondrial impairment, and synaptic dysfunction. In contrast, overexpression of parkin provides protection against cellular stresses and prevents dopaminergic neural cell loss in several animal models of PD. However, the influence of ASN on the function of parkin is largely unknown. Therefore, the aim of this study was to investigate the effect of extracellular ASN oligomers on parkin expression, S-nitrosylation, as well as its activity. For these investigations, we used rat pheochromocytoma (PC12) cell line treated with exogenous oligomeric ASN as well as PC12 cells with parkin overexpression and parkin knock-down. The experiments were performed using spectrophotometric, spectrofluorometric, and immunochemical methods. We found that exogenous ASN oligomers induce oxidative/nitrosative stress leading to parkin Snitrosylation. Moreover, this posttranslational modification induced the elevation of parkin autoubiquitination and degradation of the protein. The decreased parkin levels resulted in significant cell death, whereas parkin overexpression protected against toxicity induced by extracellular ASN oligomers. We conclude that lowering parkin levels by extracellular ASN may significantly contribute to the propagation of neurodegeneration in PD pathology through accumulation of defective proteins as a consequence of parkin degradation.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

et al. 2018

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“…However, in accordance with these results, previous studies employing higher concentrations of NO donors (i.e. 50 -200 M) resulted in either a lack of Parkin translocation or nitrosative toxic stress (19,39,40). Therefore, NO treatment at non-toxic levels appears to be critical to the induction of Parkin translocation.…”

Section: Discussionsupporting

confidence: 71%

“…PINK1 deficiency results in a near complete loss of Parkin translocation and mitophagy (6,14,15), suggesting a critical role for PINK1 in Parkin translocation via a previously unidentified mechanism. The E3 ligase activity of Parkin is stimulated by its phosphorylation (16 -18) or S-nitrosylation in the cytosol (19) or activated by phosphorylation of ubiquitin by PINK1 (20,21), which might promote the ubiquitination of various mitochondrial substrates such as voltage-dependent anion channel (VDAC), mitofusins, or Miro (22)(23)(24). Therefore, mitochondrial translocation and activation of Parkin play an essential role in priming mitochondria, which occurs via the ubiquitination of specific mitochondrial substrates, to induce autophagy by interaction with Ambra 1 (25).…”

mentioning

confidence: 99%

Nitric Oxide Induction of Parkin Translocation in PTEN-induced Putative Kinase 1 (PINK1) Deficiency

Han¹,

Kang²,

Kim³

et al. 2015

Journal of Biological Chemistry

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Background: A novel mechanism underlying mitochondrial translocation of Parkin during mitophagy is uncovered. Results: nNOS plays a significant role in Parkin translocation via interaction with full-length PINK1. Conclusion: Parkin recruitment through the interaction of nNOS with full-length PINK1 occurs during CCCP-induced mitophagy. Significance: Optimum levels of NO are sufficient for triggering the translocation of Parkin, even in the absence of PINK1, suggesting the feasibility of NO-based pharmacotherapy.

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“…Conserved cysteine residues in the R1 domain, including Cys-238, are important for maintaining the structure of the RING-finger motif of the R1 domain (56,58). Mutation of cysteine 238 to serine (C238S) prevented binding of the UBL domain to the R1 domain (Fig.…”

Section: Resultsmentioning

confidence: 99%

Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity

Ham¹,

Lee

Song

et al. 2016

Journal of Biological Chemistry

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Parkin is an E3 ligase that contains a ubiquitin-like (UBL)domain Parkinson disease (PD)3 is a neurodegenerative disorder that results from degenerated dopaminergic neurons in the substantia nigra. Most cases of PD are sporadic, and ϳ10% are familial (1). Gene mutations that are known to be responsible for the onset of the disease include PARK2 (Parkin), PARK6 (PINK1), PARK7 (DJ-1), LRRK2, and SNCA (␣-synuclein). LRRK2 and SNCA mutations are believed to cause PD through a gain of function, whereas PARK2, PARK6, and PARK7 mutations cause PD through a loss of function (2-4).Autosomal recessive early onset parkinsonism is linked to several loci, including PARK2 and PARK6 (5). The PARK2 gene encodes Parkin, an E3 ubiquitin ligase that consists of 465 amino acid residues. Parkin is composed of an ubiquitin-like (UBL) domain at the N terminus and a R1-in-between-ring (IBR)-Rind 2 (R2) motif at the C terminus (6 -8). Structurally, Parkin is a RING-type E3 ligase, but functionally it acts as a RING/HECT hybrid E3 ligase (9 -12). Parkin functions like a RING-type E3 ligase by interacting with E2 enzymes, UbcH7 and UbcH8, via the IBR domain, whereas the RING1 domain binds to substrates, allowing direct substrate ubiquitination. Parkin can also function like a HECT-type E3 ligase by catalyzing the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to the substrates via the active-site residues, Cys-431 and His-433. E2 enzymes that support Parkin function as a HECT-type E3 ligase are UbcH7, UbcH8, and Ubc13/Uev1a heterodimer (13,14).Substrates that are ubiquitinated by active Parkin include mitofusin (Mfn) 1 and 2, dynamin-related protein 1 (Drp1), voltage-dependent anion-selective channel protein 1 (VDAC1), mitochondrial Rho GTPase (Miro), and translocase of outer membrane 20 (TOM20) (15)(16)(17)(18)(19)(20). Parkin ligates these substrates with [21][22][23]. The substrates of Parkin with Lys-48-linked polyubiquitin chains are degraded by the ubiquitin proteasome system (23-26). However, those polyubiquitinated with Lys-63 or Lys-27 ubiquitin linkage recruit ubiquitin-binding adaptors such as histone deacetylase 6 (HDAC6) and p62/SQSTM1 (21,(27)(28)(29). The stability of Mfn1 and -2 and Drp1 are reduced by 30,31). TOM20 is both mono-and polyubiquitinated by Parkin by . In the case of VDAC1, Parkin catalyzes polyubiquitination with ubiquitin Lys-27 and Lys-63 linkages, which leads to recruitment of p62/SQSTM1 and subsequent induction of mitophagy (18,32).

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S-nitrosylation regulates mitochondrial quality control via activation of parkin

Cited by 83 publications

References 27 publications

Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

Nitric Oxide Induction of Parkin Translocation in PTEN-induced Putative Kinase 1 (PINK1) Deficiency

Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity

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