Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control

McLelland, Gian‐Luca; Soubannier, Vincent; Chen, Carol X; McBride, Heidi M.; Fon, Edward A.

doi:10.1002/embj.201385902

Cited by 501 publications

(636 citation statements)

References 61 publications

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“…Previously, PINK1 and Parkin were found to stimulate a distinct MDV pathway, which transports damaged mitochondrial cargo, including the E2/E3 subunits of pyruvate dehydrogenase (PDH) to the lysosome for turnover [2,3]. In contrast, the MDV pathway described in the current study is repressed by PINK1 and Parkin and appears to function independently of the PDH MDV pathway.…”

contrasting

confidence: 43%

Presenting mitochondrial antigens: PINK1, Parkin and MDVs steal the show

Roberts

Fon

2016

Cell Res

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contrasting

confidence: 43%

Presenting mitochondrial antigens: PINK1, Parkin and MDVs steal the show

Roberts

Fon

2016

Cell Res

Self Cite

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“…Mitochondria-derived Vesicles Are Not Required for LAMP1 Vacuole Formation-ROS, including H 2 O 2 , causes mitochondrial damage that is removed through the formation of MDVs, small vesicles that deliver damaged mitochondrial components to lysosomes for degradation (41,42). Consistent with this, antimycin A treatment of U2OS cells expressing GFP-Parkin causes the formation of Parkin-positive MDVs as well as of MDV positive for a matrix marker (mtHSP70) but negative for outer membrane marker TOM20 (Fig.…”

mentioning

confidence: 63%

“…and mitochondria-derived vesicles (42,43). As a consequence, genetic deletion of PINK1 impairs mitochondrial function (44).…”

Section: Mitochondrial Dysfunction Causes the Appearance Of Largementioning

confidence: 99%

Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

202

193

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Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases.A prominent feature of neurodegenerative diseases, including Parkinson disease (PD) 3 and Alzheimer disease, is the accumulation of undigested protein aggregates (1, 2). Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1, 3).In healthy cells, protein aggregates and damaged cellular components are delivered to lysosomes to be degraded through a process termed autophagy (1, 2, 4, 5). As such, autophagy plays an important neuroprotective role. Nevertheless, the defects in degradation pathways observed in neurodegenerative diseases extend well beyond alterations in autophagy. Specifically, disruption of lysosomal function has been linked to neuronal loss in several neurodegenerative diseases. For example, mutations in the lysosomal ATPase ATP13A2 cause PD, whereas lysosomal dysfunction in Gaucher disease leads to Parkinsonism and the appearance of Lewy bodies (6, 7). In addition, the ␣-synuclein-containing Lewy bodies found in PD are positive for lysosomal markers, suggesting that they represent lysosomes that failed to degrade their content (8). In fact, lysosomal alterations are a common feature of PD (8 -11). Nevertheless, the pathological consequences of a loss of lysosomal function extend well beyond PD, because a wide variety of mutations that impair lysosomes and cause the accumulation of intracellular material (lysosomal storage diseases) show features of neurodegeneration (12).A second key metabolic pathway required for neuronal survival is mitochondrial activity. In fact, mitochondrial dysfunction is a common feature of neurodegenerative diseases. For example, decreased activity of complex I of the electron transport chain (ETC) is present in a number of PD cases (13, 14), whereas amyloid ␤, Tau tangles, and Htt aggregates all cause mitochondrial dysfunction (15-17). In addition, several genes mutated in PD (including PINK1, Parkin, and DJ-1) affect mitochondrial function and turnover (18 -21), whereas deregulation of mitochon...

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“…In Drosophila, however, alterations in mitochondrial motility can be seen with manipulations of PINK1 and Parkin that do not appear to involve widespread mitophagy (15,46,58). If Miro degradation is a step toward clearance of either a segment of the OMM or mitophagy of the entire organelle (8,59), it is likely to be important, along with Mitofusin1/2 degradation, as a means to quarantine damaged mitochondria rapidly before the slower steps of autophagosome-dependent mitophagy or mitochondria-derived vesicle-based quality control.…”

Section: Discussionmentioning

confidence: 99%

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

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

128

119

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The PTEN-induced putative kinase 1 (PINK1)/Parkin pathway can tag damaged mitochondria and trigger their degradation by mitophagy. Before the onset of mitophagy, the pathway blocks mitochondrial motility by causing Miro degradation. PINK1 activates Parkin by phosphorylating both Parkin and ubiquitin. PINK1, however, has other mitochondrial substrates, including Miro (also called RhoT1 and -2), although the significance of those substrates is less clear. We show that mimicking PINK1 phosphorylation of Miro on S156 promoted the interaction of Parkin with Miro, stimulated Miro ubiquitination and degradation, recruited Parkin to the mitochondria, and via Parkin arrested axonal transport of mitochondria. Although Miro S156E promoted Parkin recruitment it was insufficient to trigger mitophagy in the absence of broader PINK1 action. In contrast, mimicking phosphorylation of Miro on T298/T299 inhibited PINK1-induced Miro ubiquitination, Parkin recruitment, and Parkin-dependent mitochondrial arrest. The effects of the T298E/T299E phosphomimetic were dominant over S156E substitution. We propose that the status of Miro phosphorylation influences the decision to undergo Parkin-dependent mitochondrial arrest, which, in the context of PINK1 action on other substrates, can restrict mitochondrial dynamics before mitophagy.is the second most common neurodegenerative disorder, and is closely linked to mitochondrial dysfunction (1, 2). Two hereditary forms of recessive PD are caused by mutations in PINK1 (PTEN-induced putative kinase 1), a Ser/Thr mitochondrial kinase, and Parkin, a cytosolic E3 ubiquitin ligase (3, 4). The realization that these proteins are in a single pathway, with PINK1 acting upstream of Parkin to influence mitochondrial properties, was a critical step in uncovering the underlying pathological mechanisms of PD (5-7). This pathway can trigger the selective autophagy of damaged mitochondria, termed mitophagy (8, 9), but additional cellular functions have also been indicated for PINK1 and Parkin (10-15). Much, however, remains unclear about how the PINK1/Parkin pathway is regulated.In current models of PINK1/Parkin mitophagy (reviewed in ref. 1), healthy mitochondria import a PINK1 precursor constitutively to the inner membrane, where it is cleaved (16-18). The cleaved form then returns to the cytoplasm and is degraded by the N-end rule pathway (19). Mitochondrial depolarization, or protein misfolding in the matrix of energized mitochondria (20), prevent the import and degradation of PINK1, resulting in the accumulation of PINK1 on the outer mitochondrial membrane (OMM) (9,21,22). Once on the OMM, PINK1 kinase activity recruits Parkin from the cytosol (8, 9). Although Parkin adopts a self-inhibited conformation in solution (23-25), it becomes fully activated in a PINK1-dependent manner on the mitochondria (9, 21). Parkin ubiquitinates numerous proteins of the OMM (26, 27), and thereby recruits autophagy-related proteins to the damaged mitochondrion for autophagosome assembly (28-30).How PINK1 recruits and activa...

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Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control

Cited by 501 publications

References 61 publications

Presenting mitochondrial antigens: PINK1, Parkin and MDVs steal the show

Presenting mitochondrial antigens: PINK1, Parkin and MDVs steal the show

Loss of Mitochondrial Function Impairs Lysosomes

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

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