Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin

Ashrafi, Ghazaleh; Schlehe, Julia S.; LaVoie, Matthew J.; Schwarz, Thomas L.

doi:10.1083/jcb.201401070

Cited by 441 publications

(436 citation statements)

References 64 publications

(127 reference statements)

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“…Robust basal mitophagy occurs in neurons (Maday et al, 2012), but it is unclear whether this constitutive process occurs through PINK1-and parkin-dependent or independent pathways (Allen et al, 2013;Bingol et al, 2014;Grenier et al, 2013;Strappazzon et al, 2014;Webster et al, 2013). By contrast, locally induced mitophagy in the axon has been shown to be dependent on both PINK1 and parkin (Ashrafi et al, 2014(Ashrafi et al, ). et al, 2012Jin et al, 2010;Meissner et al, 2011;Whitworth et al, 2008).…”

Section: Dynamics Of Mitochondrial Degradation In Neurodegenerative Dmentioning

confidence: 99%

“…However, localized damage to mitochondria in neuronal axons was also found to induce autophagosome formation locally (Ashrafi et al, 2014). As healthy mitochondria normally undergo bidirectional transport in axons, damaged mitochondria might be stalled in axons owing to release of the Milton/kinesin motor protein complex from mitochondria by PINK1 and parkin-dependent degradation of the adaptor Miro (Wang et al, 2011).…”

Section: Dynamics Of Mitochondrial Degradation In Neurodegenerative Dmentioning

confidence: 99%

“…Distal biogenesis might also be coupled to synaptic function. There is also evidence that autophagosome formation can be induced along the axon in order to clear damaged mitochondria (Ashrafi et al, 2014).…”

Section: Autophagosome Biogenesis In Neuronsmentioning

confidence: 99%

See 2 more Smart Citations

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

116

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Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.

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Section: Dynamics Of Mitochondrial Degradation In Neurodegenerative Dmentioning

confidence: 99%

Section: Dynamics Of Mitochondrial Degradation In Neurodegenerative Dmentioning

confidence: 99%

See 1 more Smart Citation

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

116

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“…To test the effects of 298/9EE on mitochondrial dynamics when endogenous PINK1 was activated, we transfected rat hippocampal neurons with either with Myc-Miro or Myc-Miro298/9EE and applied 10 μM antimycin A to activate the PINK1/Parkin pathway (51). Antimycin A caused mitochondrial arrest in both populations (Fig.…”

Section: Mirot298et299e Inhibits Parkin Effects On Mitochondrial Dynmentioning

confidence: 99%

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

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

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131

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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“…Mitochondrial dysfunction caused by overexpression of PINK1 or Parkin decreases the rate of mitochondrial transport in vitro and in vivo (36). Furthermore, a recent study using KillerRed demonstrated that local mitochondrial damage results in mitophagy in axons (37). Therefore, the acute loss of synaptic mitochondria in our model may result from defects in mitochondrial transport and/or mitophagy.…”

Section: Discussionmentioning

confidence: 90%

Mitochondrial retrograde signaling regulates neuronal function

Cagin

Duncan

Gatt

et al. 2015

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

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Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson’s disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.

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Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin

Abstract: The Parkinson’s disease–associated proteins PINK1 and Parkin mediate local mitophagy of dysfunctional mitochondria in distal neuronal axons, abrogating the need for retrograde organelle transport and ensuring rapid neuroprotection.

Cited by 441 publications

References 64 publications

Autophagosome dynamics in neurodegeneration at a glance

Autophagosome dynamics in neurodegeneration at a glance

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Mitochondrial retrograde signaling regulates neuronal function

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