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

Neurobiochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, 80336 Munich, Germany
Molecular cell (Impact Factor: 14.02). 02/2013; 49:908–921. DOI: 10.1016/j.molcel.2013.01.036
Source: PubMed


Parkin, a RING-between-RING-type E3 ubiquitin ligase associated with Parkinson's disease, has a wide neuroprotective activity, preventing cell death in various stress paradigms. We identified a stress-protective pathway regulated by parkin that links NF-κB signaling and mitochondrial integrity via linear ubiquitination. Under cellular stress, parkin is recruited to the linear ubiquitin assembly complex and increases linear ubiquitination of NF-κB essential modulator (NEMO), which is essential for canonical NF-κB signaling. As a result, the mitochondrial guanosine triphosphatase OPA1 is transcriptionally upregulated via NF-κB-responsive promoter elements for maintenance of mitochondrial integrity and protection from stress-induced cell death. Parkin-induced stress protection is lost in the absence of either NEMO or OPA1, but not in cells defective for the mitophagy pathway. Notably, in parkin-deficient cells linear ubiquitination of NEMO, activation of NF-κB, and upregulation of OPA1 are significantly reduced in response to TNF-α stimulation, supporting the physiological relevance of parkin in regulating this antiapoptotic pathway.

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    • "Furthermore, a recent study suggested that Parkin suppresses apoptosis through promoting NFkB-dependent transcriptional upregulation of the mitochondrial inner membrane protein, Opa1, thereby antagonizing apoptosis-associated cytochrome c release (Mü ller- Rischart et al., 2013). Furthermore, the latter report also suggested, rather surprisingly, that Parkin inhibits apoptosis in a PINK1-independent manner (Mü ller-Rischart et al., 2013). However , although Opa1 has been implicated in apoptosis-associated cristae junction remodeling, this event is not a major checkpoint in apoptosis and overexpression or knockdown of Opa1 does not greatly alter the threshold for apoptosis (Sheridan et al., 2008). "
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    ABSTRACT: Mitochondrial depolarization promotes Parkin- and PTEN-induced kinase 1 (PINK1)-dependent polyubiquitination of multiple proteins on mitochondrial outer membranes, resulting in the removal of defective mitochondria via mitophagy. Because Parkin mutations occur in Parkinson's disease, a condition associated with the death of dopaminergic neurons in the midbrain, wild-type Parkin is thought to promote neuronal survival. However, here we show that wild-type Parkin greatly sensitized toward apoptosis induced by mitochondrial depolarization but not by proapoptotic stimuli that failed to activate Parkin. Parkin-dependent apoptosis required PINK1 and was efficiently blocked by prosurvival members of the Bcl-2 family or knockdown of Bax and Bak. Upon mitochondrial depolarization, the Bcl-2 family member Mcl-1 underwent rapid Parkin- and PINK1-dependent polyubiquitination and degradation, which sensitized toward apoptosis via opening of the Bax/Bak channel. These data suggest that similar to other sensors of cell stress, such as p53, Parkin has cytoprotective (mitophagy) or cytotoxic modes (apoptosis), depending on the degree of mitochondrial damage. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Cell Reports
    • "Parkin has been reported previously to conjugate Ub linked via a number of different lysines including K48, K63, K27, and K29 as well as linear Ub chains and mono-Ub (Lim et al, 2005; Matsuda et al, 2006; Geisler et al, 2010; Muller-Rischart et al, 2013). Most of these studies relied exclusively on overexpression of Ub mutants or on chain-specific antibodies. "
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    ABSTRACT: Mutations in the Park2 gene, encoding the E3 ubiquitin-ligase parkin, are responsible for a familial form of Parkinson's disease (PD). Parkin-mediated ubiquitination is critical for the efficient elimination of depolarized dysfunctional mitochondria by autophagy (mitophagy). As damaged mitochondria are a major source of toxic reactive oxygen species within the cell, this pathway is believed to be highly relevant to the pathogenesis of PD. Little is known about how parkin-mediated ubiquitination is regulated during mitophagy or about the nature of the ubiquitin conjugates involved. We report here that USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for parkin-mediated mitophagy. USP8 preferentially removes non-canonical K6-linked ubiquitin chains from parkin, a process required for the efficient recruitment of parkin to depolarized mitochondria and for their subsequent elimination by mitophagy. This work uncovers a novel role for USP8-mediated deubiquitination of K6-linked ubiquitin conjugates from parkin in mitochondrial quality control.
    No preview · Article · Sep 2014 · The EMBO Journal
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    • "PINK1, a mitochondrial Ser/ Thr kinase, and Parkin, an E3 Ubiquitin ligase, were found to regulate clearance of damaged mitochondria via mitophagy (Geisler et al, 2010; Narendra et al, 2010; Vives-Bauza et al, 2010), and microtubular transport (Weihofen et al, 2009; Wang et al, 2011). However, other studies have reported additional functions of Parkin in the regulation of stress response proteins and mitochondrial biogenesis (Bouman et al, 2011; Shin et al, 2011), in promoting NF-κB signaling (Henn et al, 2007; Muller-Rischart et al, 2013), and in controlling cytochrome-c release (Berger et al, 2009). PINK1 also has additional functions, unrelated to recruiting Parkin, such as regulating mitochondrial calcium buffering (Gandhi et al, 2009; Sandebring et al, 2009; Heeman et al, 2011). "
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    ABSTRACT: Parkinson's disease (PD)-associated Pink1 and Parkin proteins are believed to function in a common pathway controlling mitochondrial clearance and trafficking. Glial cell line-derived neurotrophic factor (GDNF) and its signaling receptor Ret are neuroprotective in toxin-based animal models of PD. However, the mechanism by which GDNF/Ret protects cells from degenerating remains unclear. We investigated whether the Drosophila homolog of Ret can rescue Pink1 and park mutant phenotypes. We report that a signaling active version of Ret (Ret(MEN)(2B)) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants. Interestingly, corresponding phenotypes of park mutants were not rescued, suggesting that the phenotypes of Pink1 and park mutants have partially different origins. In human neuroblastoma cells, GDNF treatment rescues morphological defects of PINK1 knockdown, without inducing mitophagy or Parkin recruitment. GDNF also rescues bioenergetic deficits of PINK knockdown cells. Furthermore, overexpression of Ret(MEN)(2B) significantly improves electron transport chain complex I function in Pink1 mutant Drosophila. These results provide a novel mechanism underlying Ret-mediated cell protection in a situation relevant for human PD.
    Full-text · Article · Feb 2014 · The EMBO Journal
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