Cytosolic cleaved
            <scp>PINK</scp>
            1 represses
            <scp>P</scp>
            arkin translocation to mitochondria and mitophagy

Fedorowicz, Maja A.; Vries‐Schneider, Rosa L. A. de; Rüb, Cornelia; Becker, Dorothea; Huang, Yong; Zhou, Chun Hui; Wolken, Dana M. Alessi; Voos, Wolfgang; Liu, Yuhui; Przedborski, Serge

doi:10.1002/embr.201337294

Cited by 100 publications

(93 citation statements)

References 29 publications

(76 reference statements)

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“…More recently, recruitment of PARKIN by PINK1 to mitochondria has also been observed in primary neurons in a reactive oxygen speciesdependent manner (12,23). Interestingly, processed cytosolic PINK1 may also interact with cytosolic PARKIN, limiting its translocation to the mitochondria and mitophagy (15). Likewise, in the presence of MG-132, an inhibitor of the proteasome, the level of processed cytosolic PINK1 is increased significantly (24), indicating that turnover of PINK1 is through the proteasomal pathway.…”

Section: Parkinson Disease (Pd)mentioning

confidence: 92%

“…However, PINK1-deficient cells display altered calcium homeostasis at the mitochondria as well as altered mitochondrial function (14). Processed PINK1 at the inner mitochondrial membrane has also been proposed to be shuttled to the cytosol, where it is degraded by the proteasome (15). However, under conditions of mitochondrial stress such as treatment with the mitochondrial uncoupler carbonyl cyanide p-chlorophenylhydrazone (CCCP) or with the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP ϩ ), PINK1 can also regulate mitophagy in a PARKIN-dependent fashion (12, 16 -19).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

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BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

Hage

Don-Carolis

et al. 2015

Journal of Biological Chemistry

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Emerging evidence has demonstrated a growing genetic component in Parkinson disease (PD). For instance, loss-of-function mutations in PINK1 or PARKIN can cause autosomal recessive PD. Recently, PINK1 and PARKIN have been implicated in the same signaling pathway to regulate mitochondrial clearance through recruitment of PARKIN by stabilization of PINK1 on the outer membrane of depolarized mitochondria. The precise mechanisms that govern this process remain enigmatic. In this study, we identify Bcl2-associated athanogene 2 (BAG2) as a factor that promotes mitophagy. BAG2 inhibits PINK1 degradation by blocking the ubiquitination pathway. Stabilization of PINK1 by BAG2 triggers PARKIN-mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of PD. Collectively, our findings support the notion that BAG2 is an upstream regulator of the PINK1/PARKIN signaling pathway. Parkinson disease (PD)2 is the second most common neurodegenerative disorder, characterized by selective loss of the pigmented dopaminergic neurons of the substantia nigra pars compacta (1). Although most PD cases are sporadic in nature (2), mutations in several genes have been linked to familial forms of PD (reviewed in Ref.3). Indeed, these familial genes serve as important vehicles to study the potential mechanisms of pathogenesis in PD. In this regard, increasing evidence suggests that mitochondrial dysfunction may play a critical role in both the inherited and sporadic forms of PD, although the precise role of mitochondrial dysfunction in PD is unclear (4). Recently, two familial recessive PD genes, PTEN-induced putative kinase 1 (PINK1), a mitochondrially localized serine/threonine kinase gene, and PARKIN, an E3 ubiquitin ligase gene, have been identified as acting along similar pathways in regulating mitochondrial quality control in mammalian systems (5-8). These findings are supported by genetic studies in Drosophila models of PD that show that PARKIN and PINK1 function in a common pathway, with PARKIN being a downstream player of PINK1 (9 -11). A third recessive PD gene, DJ-1, associated with the regulation of oxidative stress, also regulates PINK1/PARKIN-mediated control of mitochondrial health (12).PINK1 is normally shuttled to the inner mitochondrial membrane where it is processed by multiple proteases (13). The endogenous role of PINK1 at this site is unknown. However, PINK1-deficient cells display altered calcium homeostasis at the mitochondria as well as altered mitochondrial function (14). Processed PINK1 at the inner mitochondrial membrane has also been proposed to be shuttled to the cytosol, where it is degraded by the proteasome (15). However, under conditions of mitochondrial stress such as treatment with the mitochondrial uncoupler carbonyl cyanide p-chlorophenylhydrazone (CCCP) or with the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP ϩ ), PINK1 can also regulate mitophagy in a PARKIN-dependent fashion (12, 16 -19). The framework by which this mitochondrial ...

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Section: Parkinson Disease (Pd)mentioning

confidence: 92%

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

Hage

Don-Carolis

et al. 2015

Journal of Biological Chemistry

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“…Accumulated Pink1 undergoes dimerization and intermolecular autophosphorylation at Ser228 and Ser402 thereby activating itself, leading to downstream phosphorylation events including Parkin recruitment to mitochondria (Okatsu et al, 2012. There is also a Parkin-binding role attributed to the 53kDa truncated fragment of Pink1 (Fedorowicz et al, 2014). It is known that this fragment can be stabilized via K63-linked ubiquitylation by TRAF6 (Lim et al, 2015) which might contribute to the recruitment of Parkin to mitochondria.…”

Section: Pink1 -A Major Sensor Of Mitochondrial Qualitymentioning

confidence: 99%

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

Zimmermann

Reichert

2017

Biological Chemistry

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Mitochondria are indispensable cellular organelles providing ATP and numerous other essential metabolites to ensure cell survival. Reactive oxygen species (ROS), which are formed as side reactions during oxidative phosphorylation or by external agents, induce molecular damage in mitochondrial proteins, lipids/ membranes and DNA. To cope with this and other sorts of organellar stress, a multi-level quality control system exists to maintain cellular homeostasis. One critical level of mitochondrial quality control is the removal of damaged mitochondria by mitophagy. This process utilizes parts of the general autophagy machinery, e.g. for the formation of autophagosomes but also employs mitophagy-specific factors. Depending on the proteins utilized mitophagy is divided into receptor-mediated and ubiquitin-mediated mitophagy. So far, at least seven receptor proteins are known to be required for mitophagy under different experimental conditions. In contrast to receptor-mediated pathways, the Pink-Parkin-dependent pathway is currently the best characterized ubiquitin-mediated pathway. Recently two additional ubiquitin-mediated pathways with distinctive similarities and differences were unraveled. We will summarize the current state of knowledge about these multiple pathways, explain their mechanism, and describe the regulation and crosstalk between these pathways. Finally, we will review recent evidence for the evolutionary conservation of ubiquitin-mediated mitophagy pathways.

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“…PINK1 binds to phosphoglycerate mutase family member 5 (PGAM5) in the inner mitochondrial membrane (Lu et al, 2014a) but, upon cleavage, translocates to the cytosol for proteasomal degradation (Fedorowicz et al, 2014;Yamano and Youle, 2013). Upon mitochondrial damage, parkin is recruited to damaged mitochondria downstream of PINK1, which phosphorylates Ser65 on the ubiquitin-like (UBL) domain of parkin (Kondapalli et al, 2012;Shiba-Fukushima et al, 2012) and Ser65 on ubiquitin, leading to parkin activation (Kane et al, 2014;Kazlauskaite et al, 2014;Koyano et al, 2014;Ordureau et al, 2014;Zhang et al, 2014).…”

Section: Dynamics Of Mitochondrial Degradation In Neurodegenerative Dmentioning

confidence: 99%

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

113

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Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.

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Cytosolic cleaved PINK 1 represses P arkin translocation to mitochondria and mitophagy

Cited by 100 publications

References 29 publications

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

Autophagosome dynamics in neurodegeneration at a glance

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