The E3 Ligase Parkin Maintains Mitochondrial Integrity by Increasing Linear Ubiquitination of NEMO

Müller-Rischart, Anne Kathrin; Pilsl, Anna; Beaudette, Patrick; Patra, Maria; Hadian, Kamyar; Funke, Maria; Peis, Regina; Deinlein, Alexandra; Schweimer, Carolin; Kuhn, Peer‐Hendrik; Lichtenthaler, Stefan F.; Motori, Elisa; Hrelia, Silvana; Wurst, Wolfgang; Trümbach, Dietrich; Langer, Thomas; Krappmann, Daniel; Dittmar, Gunnar; Tatzelt, Jörg; Winklhofer, Konstanze F.

doi:10.1016/j.molcel.2013.01.036

Cited by 187 publications

(172 citation statements)

References 34 publications

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“…In our studies, we found that, unlike the WT RBR domain, a mitochondrially- [44]. Another recent study reported a new function for Parkin showing that in response to cellular stress, Parkin is recruited to the linear ubiquitin chain assembly complex, and increases linear ubiquitylation of NEMO, a process that is critical for the activation of the NF-κB pathway [45]. Our finding that Parkin can associate with ubiquitin chains attached to substrates may provide an explanation for these observations.…”

Section: Parkin Binds K63-linked Ubiquitin Chainssupporting

confidence: 56%

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

Zheng

Hunter

2013

Cell Res

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Pink1, a mitochondrial kinase, and Parkin, an E3 ubiquitin ligase, function in mitochondrial maintenance. Pink1 accumulates on depolarized mitochondria, where it recruits Parkin to mainly induce K63-linked chain ubiquitination of outer membrane proteins and eventually mitophagy. Parkin belongs to the RBR E3 ligase family. Recently, it has been proposed that the RBR domain transfers ubiquitin to targets via a cysteine~ubiquitin enzyme intermediate, in a manner similar to HECT domain E3 ligases. However, direct evidence for a ubiquitin transfer mechanism and its importance for Parkin's in vivo function is still missing. Here, we report that Parkin E3 activity relies on cysteinemediated ubiquitin transfer during mitophagy. Mutating the putative catalytic cysteine to serine (Parkin C431S) traps ubiquitin, and surprisingly, also abrogates Parkin mitochondrial translocation, indicating that E3 activity is essential for Parkin translocation. We found that Parkin can bind to K63-linked ubiquitin chains, and that targeting K63-mimicking ubiquitin chains to mitochondria restores Parkin C431S localization. We propose that Parkin translocation is achieved through a novel catalytic activity coupled mechanism.

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Section: Parkin Binds K63-linked Ubiquitin Chainssupporting

confidence: 56%

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

Zheng

Hunter

2013

Cell Res

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“…Because previous studies have implicated single heterozygous mutations in PARK2 and PINK1 as possible risk factors for developing parkinsonism,51 we performed a comprehensive mutation analysis of both genes in our patients, but failed to identify pathogenic variants. Notably, a direct link was recently established between Parkin and OPA1, through linear ubiquitination of NF‐kB essential modulator, which upregulates the expression of OPA1, promoting mitochondrial integrity and protecting from stress‐induced cell death 52. Conversely, alterations in both mitochondrial morphology and ATP production caused by either Parkin or PINK1 loss of function can be rescued by overexpressing the mitochondrial fusion proteins MFN2 and OPA1 53.…”

Section: Discussionmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

160

106

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ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

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“…The realization that these proteins are in a single pathway, with PINK1 acting upstream of Parkin to influence mitochondrial properties, was a critical step in uncovering the underlying pathological mechanisms of PD (5)(6)(7). This pathway can trigger the selective autophagy of damaged mitochondria, termed mitophagy (8,9), but additional cellular functions have also been indicated for PINK1 and Parkin (10)(11)(12)(13)(14)(15). Much, however, remains unclear about how the PINK1/Parkin pathway is regulated.…”

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confidence: 99%

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

132

119

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The PTEN-induced putative kinase 1 (PINK1)/Parkin pathway can tag damaged mitochondria and trigger their degradation by mitophagy. Before the onset of mitophagy, the pathway blocks mitochondrial motility by causing Miro degradation. PINK1 activates Parkin by phosphorylating both Parkin and ubiquitin. PINK1, however, has other mitochondrial substrates, including Miro (also called RhoT1 and -2), although the significance of those substrates is less clear. We show that mimicking PINK1 phosphorylation of Miro on S156 promoted the interaction of Parkin with Miro, stimulated Miro ubiquitination and degradation, recruited Parkin to the mitochondria, and via Parkin arrested axonal transport of mitochondria. Although Miro S156E promoted Parkin recruitment it was insufficient to trigger mitophagy in the absence of broader PINK1 action. In contrast, mimicking phosphorylation of Miro on T298/T299 inhibited PINK1-induced Miro ubiquitination, Parkin recruitment, and Parkin-dependent mitochondrial arrest. The effects of the T298E/T299E phosphomimetic were dominant over S156E substitution. We propose that the status of Miro phosphorylation influences the decision to undergo Parkin-dependent mitochondrial arrest, which, in the context of PINK1 action on other substrates, can restrict mitochondrial dynamics before mitophagy.is the second most common neurodegenerative disorder, and is closely linked to mitochondrial dysfunction (1, 2). Two hereditary forms of recessive PD are caused by mutations in PINK1 (PTEN-induced putative kinase 1), a Ser/Thr mitochondrial kinase, and Parkin, a cytosolic E3 ubiquitin ligase (3, 4). The realization that these proteins are in a single pathway, with PINK1 acting upstream of Parkin to influence mitochondrial properties, was a critical step in uncovering the underlying pathological mechanisms of PD (5-7). This pathway can trigger the selective autophagy of damaged mitochondria, termed mitophagy (8, 9), but additional cellular functions have also been indicated for PINK1 and Parkin (10-15). Much, however, remains unclear about how the PINK1/Parkin pathway is regulated.In current models of PINK1/Parkin mitophagy (reviewed in ref. 1), healthy mitochondria import a PINK1 precursor constitutively to the inner membrane, where it is cleaved (16-18). The cleaved form then returns to the cytoplasm and is degraded by the N-end rule pathway (19). Mitochondrial depolarization, or protein misfolding in the matrix of energized mitochondria (20), prevent the import and degradation of PINK1, resulting in the accumulation of PINK1 on the outer mitochondrial membrane (OMM) (9,21,22). Once on the OMM, PINK1 kinase activity recruits Parkin from the cytosol (8, 9). Although Parkin adopts a self-inhibited conformation in solution (23-25), it becomes fully activated in a PINK1-dependent manner on the mitochondria (9, 21). Parkin ubiquitinates numerous proteins of the OMM (26, 27), and thereby recruits autophagy-related proteins to the damaged mitochondrion for autophagosome assembly (28-30).How PINK1 recruits and activa...

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The E3 Ligase Parkin Maintains Mitochondrial Integrity by Increasing Linear Ubiquitination of NEMO

Cited by 187 publications

References 34 publications

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

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