Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress

Muqit, Miratul M. K.; Abou‐Sleiman, Patrick M.; Saurin, Adrian T.; Harvey, Kirsten; Gandhi, Sonia; Deas, Emma; Eaton, Simon; Smith, Martin D.; Venner, Kerrie; Matilla, Antoni; Healy, Daniel G.; Gilks, William P.; Lees, Andrew J.; Holton, Janice L.; Révész, Tamás; Parker, Peter J.; Harvey, Richard J.; Wood, Nicholas W.; Latchman, David S.

doi:10.1111/j.1471-4159.2006.03845.x

Cited by 149 publications

(139 citation statements)

References 43 publications

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“…Finally, it has been reported that there is an increased expression of PINK1 52 protein in PD brains [29]. If our model is correct, this suggests that in PD there may be a deficit in mitophagy by virtue of the fact that cleaved PINK1 may prevent Parkin translocation, hence hampering the elimination of damaged mitochondria.…”

Section: Discussionmentioning

confidence: 50%

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

Fedorowicz

Vries‐Schneider

Rüb³

et al. 2013

EMBO Reports

100

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PINK1 is a mitochondrial kinase proposed to have a role in the pathogenesis of Parkinson's disease through the regulation of mitophagy. Here, we show that the PINK1 main cleavage product, PINK1 52, after being generated inside mitochondria, can exit these organelles and localize to the cytosol, where it is not only destined for degradation by the proteasome but binds to Parkin. The interaction of cytosolic PINK1 with Parkin represses Parkin translocation to the mitochondria and subsequent mitophagy. Our work therefore highlights the existence of two cellular pools of PINK1 that have different effects on Parkin translocation and mitophagy.

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Section: Discussionmentioning

confidence: 50%

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

Fedorowicz

Vries‐Schneider

Rüb³

et al. 2013

EMBO Reports

100

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“…The prediction programs iPSORT (http://biocaml.org/ipsort/ iPSORT/), MitoProt II (ftp://ftp.ens.fr/pub/molbio/), and TargetP (http://www.cbs.dtu.dk/sevices/TargetP) predict a MTS within the N-terminal end of human PINK1 contained in amino acids 1-30, 1-34, or 1-76, respectively. Consistent with this notion, it has been shown that the first 93 amino acids (6) and the first 34 amino acids (20) suffice to target GFP to the mitochondria. To determine whether this region of PINK1 is required for its importation into mitochondria, we constructed cDNA plasmids expressing PINK1 truncated at its first 34, 91, or 150 amino acids (Fig.…”

Section: Resultsmentioning

confidence: 72%

“…In keeping with these results, Haque et al (22) and Takatori et al (23) have also found that, upon deletion of amino acids 1-111 or 1-108, respectively, PINK1 could no longer be imported into the mitochondria. Collectively, these findings indicate that the Nterminal end of PINK1 contains the MTS and that its composition is complex and not limited to the first 34 amino acids (20).…”

Section: Resultsmentioning

confidence: 77%

“…Although it is agreed that PINK1 is a mitochondrialtargeted protein, PINK1 has been reported to reside in the inner mitochondrial membrane (IMM) (6,7,9,20), the mitochondrial intermembrane space (IMS) (6,8,9), the outer mitochondrial membrane (OMM) (7), and even the cytoplasm (21-24). Furthermore, the tumor necrosis factor type 1 receptor-associated protein (TRAP1) and the serine protease HtrA2/Omi have been identified as putative PINK1 substrates (8, 9).…”

mentioning

confidence: 99%

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The kinase domain of mitochondrial PINK1 faces the cytoplasm

Zhou

Huang

Shao

et al. 2008

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

282

259

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Mutations in PTEN-induced putative kinase 1 (PINK1) are a cause of autosomal recessive familial Parkinson's disease (PD). Efforts in deducing the PINK1 signaling pathway have been hindered by controversy around its subcellular and submitochondrial localization and the authenticity of its reported substrates. We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. Although deletion of the transmembrane domain disrupts this topology, common PD-linked PINK1 mutations do not. These results are critical in rectifying the location and orientation of PINK1 in mitochondria, and they should help decipher its normal physiological function and potential pathogenic role in PD.parkin ͉ Parkinson's disease ͉ mitochondria ͉ topology P arkinson's disease (PD), the second most common neurodegenerative disorder, is a sporadic condition that can occasionally be inherited (1). The rationale for studying the rare genetic forms of PD is based on the phenotypic similarity between the familial and sporadic forms of the disease, implying that the two share important pathogenic mechanisms. Among the different gene products associated with familial PD (2), PTEN-induced putative kinase-1 (PINK1) is localized to the mitochondria (3-10), an organelle strongly linked to PD pathogenesis. Although recessively inherited PD mutations in PINK1 are found throughout the protein, they are most commonly found in the only recognized functional domain of PINK1 (3,11,12), which is a serine/threonine kinase domain similar to that in the Ca 2ϩ /calmodulin kinase family (13,14). Overexpression of wild-type PINK1 can rescue the phenotype caused by PINK1 mutations in Drosophila (15, 16), supporting the notion that the mutated allele gives rise to a loss-of-function phenotype.Human PINK1 is a 581-aa polypeptide with a predicted N-terminal mitochondrial targeting signal (MTS), consistent with the observation that PINK1 localizes to mitochondria (Fig. 1A) (3-10). Loss-of-function mutations in the gene encoding parkin (an E3 ubiquitin ligase) cause the most frequent forms of recessive familial PD (17). In Drosophila, parkin is thought to operate within the same molecular pathway as PINK1 to modulate mitochondrial morphology (15,16,18), an intriguing observation given the fact that parkin has been reported to essentially be cytosolic (19).Both the subcellular and submitochondrial locations of PINK1 and the authenticity of its reported substrates have been controversial. Although it is agreed that PINK1 is a mitochondrialtargeted protein, PINK1 has been reported to reside in the inner mitochondrial membrane (IMM) (6,7,9,20), the mitochondrial intermembrane space (IMS) (6,8,9), the outer mitochondrial membrane (OMM) (7), and even the cytoplasm (21-24). Furthermore, the tumor necrosis factor type 1 receptor-associated protein (TRAP1) and the serine protease HtrA2/Omi have been identified as putative PINK1 substrates (8, 9). Although TRAP1 is localized mainly i...

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“…Ultrastructural ana lysis by the same authors further revealed that DJ-1 localizes to the halo, but was absent inside the core of these LB-like inclusions, in the brains of these mice [149]. Although investigators have shown that the protein product from the PINK1 gene mutation, which associates with PARK6-linked PD localizes to LBs in human PD brains [151], a lack of post-mortem material makes it currently unknown whether patients with DJ-1 mutations and who display parkinsonian symptoms, form LBs or Lewy neurites. The study by Jin and co-workers informs on this by suggesting that DJ-1 might play a significant part in mitochondrial dysfunction and in promoting LB formation in PD [149].…”

Section: A U T H O R P R O O F Review Pienaar Dexter and Burkhardmentioning

confidence: 93%

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

Pienaar¹,

Dexter²,

Burkhard³

2010

Expert Review of Proteomics

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Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress

Cited by 149 publications

References 43 publications

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

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

The kinase domain of mitochondrial PINK1 faces the cytoplasm

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

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