Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy

Lee, Joo‐Yong; Nagano, Yoshito; Taylor, J. Paul; Lim, Kah‐Leong; Yao, Tso‐Pang

doi:10.1083/jcb.201001039

Cited by 489 publications

(496 citation statements)

References 22 publications

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“…It is also reported that Parkin-mediated mitochondrial ubiquitination recruits the ubiquitin-binding autophagic adaptors p62 and HDAC6 to mitochondria and that a deficiency of either inhibits Parkin-dependent mitophagy (Geisler et al, 2010;Lee et al, 2010). In addition, Geisler et al (2010) identified voltagedependent anion channel 1 (VDAC1), a channel protein in the mitochondrial outer membrane, as a target for Parkin-mediated ubiquitination and turnover of damaged mitochondria.…”

Section: Parkin Remodels Mitochondria By Ubquitinating Its Mitochondrmentioning

confidence: 99%

“…Subsequent studies discovered that PINK1 is selectively translocated to mitochondria damaged by CCCP and activates their degradation via Parkin (Matsuda et al, 2010;Narendra et al, 2010a;Vives-Bauza et al, 2010). Moreover, in CCCP-treated cells, Parkin promotes the ubiquitination of impaired mitochondria and the expression of dominant-negative ubiquitin mutants prevents subsequent mitochondrial clearance, demonstrating the functional link between Parkin, ubiquitin, and mitophagy (Geisler et al, 2010;Lee et al, 2010;Matsuda et al, 2010).…”

Section: Parkin Remodels Mitochondria By Ubquitinating Its Mitochondrmentioning

confidence: 99%

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PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

Koh

Chung

2012

Molecules and Cells

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Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by an agedependent selective loss of dopaminergic (DA) neurons. Although most PD cases are sporadic, more than 20 responsible genes in familial cases were identified recently. Genetic studies using Drosophila models demonstrate that PINK1, a mitochondrial kinase encoded by a PD-linked gene PINK1, is critical for maintaining mitochondrial function and integrity. This suggests that mitochondrial dysfunction is the main cause of PD pathogenesis. Further genetic and cell biological studies revealed that PINK1 recruits Parkin, an E3 ubiquitin ligase encoded by another PD-linked gene parkin, to mitochondria and regulates the mitochondrial remodeling process via the Parkin-mediated ubiquitination of various mitochondrial proteins. PINK1 also directly phosphorylates the mitochondrial proteins Miro and TRAP1, subsequently inhibiting mitochondrial transport and mitochondrial oxidative damage, respectively. Moreover, recent Drosophila genetic analyses demonstrate that the neuroprotective molecules Sir2 and FOXO specifically complement mitochondrial dysfunction and DA neuron loss in PINK1 null mutants, suggesting that Sir2 and FOXO protect mitochondria and DA neurons downstream of PINK1. Collectively, these recent results suggest that PINK1 plays multiple roles in mitochondrial quality control by regulating its mitochondrial, cytosolic, and nuclear targets.

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Section: Parkin Remodels Mitochondria By Ubquitinating Its Mitochondrmentioning

confidence: 99%

Section: Parkin Remodels Mitochondria By Ubquitinating Its Mitochondrmentioning

confidence: 99%

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

Koh

Chung

2012

Molecules and Cells

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“…77 Parkin mediates formation of two types of polyubiquitin chains: 68 lysine (K) 48 linkage associated with proteosomal degradation of the substrate; and lysine (K) 63 linkage associated with autophagic degradation. 48,78 Although Parkin-mediated polyubiquitination of mitochondrial substrates is likely to be the mechanism by which it triggers mitophagy, 45,79 ( Figure 4b) the details of how this happens remain uncertain. In one model, Parkin mediates formation of K48 chains on specific mitochondrial outer membrane proteins and it is the proteosomal degradation of these proteins that triggers mitophagy.…”

Section: Parkin Promotes Ubiquitination Of Mitochondrial Proteinsmentioning

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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“…The hallmark for many forms of selective organelle autophagy is surface ubiquitination. In mitophagy, dysfunctional mitochondria are first ubiquitinated before being turned over 10,11,13,14,20 . Artificial ubiquitination of peroxisomal outer-membrane proteins can also lead to pexophagy in mammalian cell cultures 21,22 .…”

Section: Spatiotemporally Controlled Induction Of Lysosomal Damagementioning

confidence: 99%

“…In this pathway, a loss of mitochondrial membrane potential is sensed by the PINK1/parkin machinery, leading to specific ubiquitination of outer-membrane proteins on damaged mitochondria [9][10][11] . This ubiquitin tag then allows the autophagic machinery and the autophagy adaptor protein p62 to specifically recognize and turnover a dysfunctional mitochondrion within the complex cellular environment 10,[12][13][14][15] .…”

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confidence: 99%

Spatiotemporally controlled induction of autophagy-mediated lysosome turnover

et al. 2013

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Lysosomes are the major degradative compartments within cells, harbouring a wide variety of hydrolytic enzymes within their lumen. Release of lysosomal hydrolases from lysosomes into the cell cytoplasm results in cell death. Here we report that damaged lysosomes undergo autophagic turnover. Using a light-induced lysosome impairing scheme that can be controlled spatially and temporally within a cell, we show that damaged lysosomes are selectively ubiquitinated, recruit autophagic proteins and are eventually incorporated into autolysosomes for degradation. We propose that autophagic removal of lysosomes, which we term lysophagy, is a surveillance mechanism that alleviates cells from the adverse effects of lysosomal damage. We envision our method to induce lysosomal damage will enable detailed molecular studies of the lysophagy pathway in the future.

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Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy

Abstract: Parkin catalyzes mitochondrial ubiquitination, recruiting autophagic components that clear damaged mitochondria. Defects in this pathway are implicated in Parkinson's disease.

Cited by 489 publications

References 22 publications

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

The pathways of mitophagy for quality control and clearance of mitochondria

Spatiotemporally controlled induction of autophagy-mediated lysosome turnover

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