Parkin stabilizes PINK1 through direct interaction

Shiba, Kahori; Arai, Takashi; Sato, Shigeto; Kubo, Shinichiro; Ohba, Yusuke; Mizuno, Yoshikuni; Hattori, Nobutaka

doi:10.1016/j.bbrc.2009.04.006

Cited by 64 publications

(48 citation statements)

References 8 publications

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“…Although the kinase activity of PINK1 is required for it to recruit Parkin, it is unclear as to how this occurs. One hypothesis is that PINK1 binding to 45,75 and phosphorylation 35,71,76 of Parkin serves to activate that enzyme and cause its translocation, but this remains controversial. Alternatively, it is possible that PINK1 phosphorylates an unknown substrate, and it is the primed substrate, not PINK1 per se, that binds to and recruits Parkin.…”

Section: The Pink1/parkin Pathway Of Mitophagymentioning

confidence: 99%

The pathways of mitophagy for quality control and clearance of mitochondria

2012

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Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration. Facts Mitophagy mediates clearance of damaged mitochondria, and is also involved in the removal of mitochondria from maturing erythrocytes and eliminating sperm-derived mitochondria after fertilization. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the core autophagic machinery to mitochondria for their selective removal. A pathway containing PTEN-induced putative protein kinase 1 (PINK1) and Parkin responds to loss of mitochondrial membrane potential by targeting damaged mitochondria for clearance. The PINK1/Parkin pathway is triggered when PINK1 is stabilized on the outer membrane of damaged mitochondria, where it facilitates recruitment of cytosolic Parkin. Damaged mitochondria are prevented from moving and fusing with the mitochondrial reticulum in preparation for their mitophagic clearance. Open QuestionsHow distinct are the mitophagy pathways triggered by different stimuli or conditions?To what extent does Parkin activate mitophagy by causing the degradation of mitochondrial surface proteins or hyperubiquitinating the mitochondrial surface? How do PINK1 and Parkin interact with one another and with substrates on the mitochondrial surface in causing mitophagy? In contrast to the remarkable conservation of the core autophagic machinery, why are mitophagy-specific genes so little conserved between yeast and mammals? How best should mitophagy be triggered by researchers probing physiologically relevant pathways?The mitochondrion is an important actor in the life of a eukaryotic cell, but, like all good actors, a mitochondrion needs to exit the stage at the right time. Mitophagy removes mitochondria once they have played their part. This artic...

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Section: The Pink1/parkin Pathway Of Mitophagymentioning

confidence: 99%

The pathways of mitophagy for quality control and clearance of mitochondria

2012

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“…Germane to this possibility, we wondered whether cytosolic PINK1 52 might bind to cytosolic Parkin, and in doing so, whether it might prevent Parkin translocation to mitochondria and ensuing mitophagy. To test this question, we first performed co-immunoprecipitation experiments of whole cell extracts and confirmed that PINK1 physically interacts with Parkin [5,26,27] (Fig 2A). Since specific domains of Parkin are necessary to allow cytosolic Parkin to translocate to mitochondria [27,28], we next sought to determine the PINK1 and Parkin binding domains.…”

Section: Pink1 52 Binds Parkinmentioning

confidence: 99%

“…To test this question, we first performed co-immunoprecipitation experiments of whole cell extracts and confirmed that PINK1 physically interacts with Parkin [5,26,27] (Fig 2A). Since specific domains of Parkin are necessary to allow cytosolic Parkin to translocate to mitochondria [27,28], we next sought to determine the PINK1 and Parkin binding domains. Accordingly, immunoprecipitation experiments with several truncated forms of PINK1 carrying a C-terminal Flag-tag were performed (Fig 2A).…”

Section: Pink1 52 Binds Parkinmentioning

confidence: 99%

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

Fedorowicz

Vries‐Schneider

Rüb³

et al. 2013

EMBO Reports

102

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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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“…Parkin requires PINK1 (PTENinduced putative kinase 1)-dependent phosphorylation for its recruitment to damaged mitochondria [53]. Interestingly, PINK1 is stabilized by its interaction with Parkin and enhances basal and starvation-induced autophagy through binding with Beclin-1 [54,55]. …”

Section: Autophagy In Quality Controlmentioning

confidence: 99%

Autophagy: for better or for worse

et al. 2011

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Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism protecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numerous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immunity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.

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Parkin stabilizes PINK1 through direct interaction

Cited by 64 publications

References 8 publications

The pathways of mitophagy for quality control and clearance of mitochondria

The pathways of mitophagy for quality control and clearance of mitochondria

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

Autophagy: for better or for worse

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