Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy

Chan, Nickie C.; Salazar, Anna M.; Pham, Anh H.; Sweredoski, Michael J.; Kolawa, Natalie J.; Graham, R.L.; Hess, Sonja; Chan, David C.

doi:10.1093/hmg/ddr048

Cited by 883 publications

(990 citation statements)

References 42 publications

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“…These data suggest that PINK1 and Parkin induce the ubiquitination of VDAC1 to recruit the autophagic components p62 and HDAC6 for the specific turnover of damaged mitochondria. However, other studies report that p62 and VDAC1 are dispensable for Parkin-induced mitophagy (Narendra et al, 2010b; and that the outer membrane protein degradation caused by the ubiquitin -proteasome system is critical for Parkin-mediated mitophagy (Chan et al, 2011). We expect that more important details of the molecular mechanism of mitophagy mediated by the PINK1 -Parkin pathway will be revealed soon.…”

Section: Parkin Remodels Mitochondria By Ubquitinating Its Mitochondrmentioning

confidence: 90%

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: 90%

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

Koh

Chung

2012

Molecules and Cells

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“…However, although loss of Mitofusin is necessary for mitophagy to proceed, it is not by itself sufficient to trigger mitophagy and PINK1 and Parkin can initiate mitophagy in cells lacking Mitofusin. 56,68 Mitochondrial fragmentation in the absence of Mitofusin thus appears to be a permissive rather than a triggering event.…”

Section: The Pink1/parkin Pathway Of Mitophagymentioning

confidence: 99%

“…In support of this model, inhibition of proteosome activity prevents mitophagy of damaged mitochondria. 56,68 A proteomic study in HeLa cells revealed Parkin-and proteosome-dependent degradation of Miro, Mitofusin, hFis1, and Tom70, as well as others, before mitophagy. However, as mentioned above, while proteosomal elimination of Mitofusin is required, it is not sufficient for initiation of mitophagy.…”

Section: Parkin Promotes Ubiquitination Of Mitochondrial Proteinsmentioning

confidence: 99%

“…Moreover, proteosome inhibition in Mitofusin-null cells prevents mitophagy, indicating that Mitofusin is not the key target. 68 Therefore, it is not clear whether the degradation of these candidate proteins, if any, leads to activation of mitophagy or if they are merely permissive for mitophagy by, among other things, arresting motility and inducing fragmentation (Figure 4bi). In a second model, Parkin causes formation of K63 (or 27)-linked ubiquitin chains on mitochondrial outer surface, and these ubiquitin chains, rather than inducing proteosomal degradation, initiate a signaling cascade that activates mitophagy (Figure 4bi).…”

Section: Parkin Promotes Ubiquitination Of Mitochondrial Proteinsmentioning

confidence: 99%

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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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“…Importantly, Parkin has been shown to target some mitochondrial proteins for proteasomal degradation independently of mitophagy 37,38 . Therefore, multiple approaches should be used, at least in initial experiments, to verify the method is functional.…”

Section: Assessment Of Mitophagymentioning

confidence: 99%

Depletion of mitochondria in mammalian cells through enforced mitophagy

et al. 2016

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Mitochondria are not only the "power-house" of the cell, but are also involved in a multitude of processes that include calcium storage, cell-cycle and cell-death. Traditional means to investigate mitochondrial importance in a given cellular process have centred upon depletion of mitochondrial DNA (mtDNA) through chemical or genetic means. While these methods severely disrupt mitochondrial electron transport chain, mtDNA-depleted cells still maintain mitochondria and many mitochondrial functions. Here, we describe a straightforward protocol to generate mammalian cell populations with low to non-detectable levels of mitochondria. Ectopic expression of the ubiquitin E3 ligase Parkin, combined with short-term mitochondrial uncoupler treatment, engages widespread mitophagy, and effectively eliminates mitochondria. In this protocol, we explain how to generate mitochondria-depleted cells and a variety of methods to confirm mitochondrial clearance. Furthermore, we describe culture conditions to maintain mitochondrial-depleted cells with minimal loss of viability for longitudinal studies. This method should prove useful to investigate the importance of mitochondria in a variety of biological processes.

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Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy

Cited by 883 publications

References 42 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

Depletion of mitochondria in mammalian cells through enforced mitophagy

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