Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin

Tanaka, Atsushi; Cleland, Megan M.; Xu, Shanshan; Narendra, Derek P.; Suen, Der-Fen; Karbowski, Mariusz; Youle, Richard J.

doi:10.1083/jcb.201007013

Cited by 1,223 publications

(1,212 citation statements)

References 57 publications

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“…66 Although similar studies in mammalian systems have produced contradictory results, 64,67 the findings in the fly indicate that PINK1 and Parkin promote fission. Consistent with this conclusion, mammalian and fly studies indicate that upon mitochondrial depolarization, Parkin translocates to mitochondria and causes polyubiquitination of Mitofusin, targeting it for removal from the mitochondrial membrane by the p97 AAA-ATPase and subsequent proteosomal degradation [55][56][57] ( Figure 4bi). Degradation of Mitofusin prevents damaged mitochondria from fusing with the functional mitochondrial network and is essential for their subsequent degradation by mitophagy.…”

Section: The Pink1/parkin Pathway Of Mitophagysupporting

confidence: 61%

“…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%

“…The autophagosome fuses with the lysosome forming an autolysosome in which the mitochondrial cargo is degraded with the mitochondrial reticulum, the depolarized daughter mitochondrion is unlikely to undergo fusion and is often degraded through mitophagy. Depolarization causes the loss of Opa1 54 and Mitofusins (Mfn1 and 2), [55][56][57] proteins necessary for the fusion of the inner and outer membranes of mitochondria, and thereby promotes mitochondrial fragmentation. In agreement with the essential role of fission in mitophagy, a yeast genetic screen revealed that Dnm1, the yeast homolog of Drp1, is essential for mitophagy.…”

Section: Modulation Of Mitochondrial Dynamics Before the Onset Of Mitmentioning

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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Section: The Pink1/parkin Pathway Of Mitophagysupporting

confidence: 61%

Section: The Pink1/parkin Pathway Of Mitophagymentioning

confidence: 99%

Section: Modulation Of Mitochondrial Dynamics Before the Onset Of Mitmentioning

confidence: 99%

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The pathways of mitophagy for quality control and clearance of mitochondria

2012

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“…Moreover, PINK1 deficiency or point mutations induce mitochondrial fragmentation in immortal or primary human neuronal cells, indicating that PINK1 and Parkin inhibit mitochondrial fission in human neuronal cells (Exner et al, 2007;Kim et al, 2008a). Recently, several groups reported that the pro-mitochondrial fusion protein Marf and its human homolog, mitofusin (Mfn), are specifically ubiquitinated and degraded by Parkin in both human and Drosophila systems (Gegg et al, 2010;Tanaka et al, 2010;Ziviani et al, 2010). Therefore, the exact molecular mechanisms underlying these different mitochondrial remodeling patterns are expected to be elucidated soon.…”

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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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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“…When mitochondria are damaged by CCCP and lose membrane potential, the kinase PTEN-induced putative kinase protein 1 (PINK1) accumulates and recruits the E3 ubiquitin ligase parkin specifically to the damaged mitochondrion (41). Parkin ubiquitinates mitochondrial proteins including mitofusins, and they cause mitochondria to be engulfed by double-layered isolation membranes (42). Recent studies have indicated the existence of specific adaptors, such as p62 and NBR1, which link with the ubiquitinated targets to LC3-II of autophagosomal membranes (43,44).…”

Section: Ubiquitin-modified Peroxisomes Were Degraded Selectivelymentioning

confidence: 99%

Peroxisome degradation in mammals

2011

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SummaryThis review summarizes the historical aspects of the study of peroxisome degradation in mammalian cells. Peroxisomes have diverse metabolic roles in response to environmental changes and are degraded in a preferential manner, by comparison with cytosolic proteins. This review introduces three hypotheses on the degradation mechanisms: (a) the action of the peroxisomespecific Lon protease; (b) the membrane disruption effect of 15-lipoxygenase; and (c) autophagy that sequesters and degrades the organelles by lysosomal enzymes. Among these hypotheses, autophagy is now recognized as the most important mechanism for excess peroxisome degradation. One of the most striking characteristics of peroxisomes is that they are markedly proliferated in the liver by the administration of hypolipidemic drugs and industrial plasticizers. The effects of these substances were fully reversed after withdrawal of the substances, and most of the excess peroxisomes were selectively degraded and recovered to a normal number and size. Autophagic degradation of peroxisomes has been examined using this characteristic phenomenon. Excessive peroxisome degradation that occurs after cessation of hypolipidemic drugs has been extensively investigated biochemically and morphologically. The evidence shows that the degradation of excess peroxisomes and peroxisomal enzymes is inhibited by 3-methyladenine (3-MA), a specific inhibitor of autophagy. Furthermore, in liver-specific autophagy-deficient mice, rapid removal of peroxisomes was exclusively impaired, and degradation of peroxisomal enzymes was not detected. Thus, the significant contribution of autophagic machinery to peroxisomal degradation in mammals was confirmed. However, the important question of the mechanism for the selective recognition of peroxisomes by autophagosomes remains to be fully elucidated.

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Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin

Abstract: The Parkin ubiquitin ligase marks the mitofusins Mfn1 and Mfn2 for proteasome-dependent degradation, promoting disposal of damaged mitochondria by preventing their fusion with healthy organelles.

Cited by 1,223 publications

References 57 publications

The pathways of mitophagy for quality control and clearance of mitochondria

The pathways of mitophagy for quality control and clearance of mitochondria

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

Peroxisome degradation in mammals

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