PINK1-mediated Phosphorylation of Miro Inhibits Synaptic Growth and Protects Dopaminergic Neurons in Drosophila

Tsai, Pei I.; Course, Meredith M.; Lovas, Jonathan R.; Hsieh, Chung Han; Babic, Milos; Zinsmaier, Konrad E.; Wang, Xinnan

doi:10.1038/srep06962

Cited by 41 publications

(42 citation statements)

References 45 publications

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“…Therefore, although PINK1-mediated S156 phosphorylation is not required for Miro degradation, the functional effect of mutating this site can be revealed when Parkin activity is low to moderate. The in vivo significance of the phosphorylation site was observed in Drosophila (46) and is also supported by our previous observations on mitochondrial motility in hippocampal neurons (15).…”

Section: Discussionsupporting

confidence: 82%

“…We do not know whether the degradation of Miro in mammalian cells under normal physiological conditions is always an early "pro-clearance" step in a series that will ultimately produce mitophagy, or if there are levels of PINK1 activation that will stop the process with Miro degradation and a decrease in mitochondrial motility. 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%

“…Moreover, Miro phosphorylations are needed for the survival of dopaminergic neurons and the proper development of the neuromuscular junction in Drosophila (46). Miro is thus a good candidate in which to explore the functional roles of PINK1 phosphorylations of Parkin substrates.…”

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

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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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

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

128

119

View full text Add to dashboard Cite

show abstract

“…Expression of phospho-resistant Miro in a Miro null mutant background phenocopied a subset of phenotypes of PINK1 null flies. Specifically, phospho-resistant Miro increased mitochondrial movement and synaptic growth at larval neuromuscular junctions, and decreased the number of dopaminergic neurons in adult brains (12).…”

Section: Editorialmentioning

confidence: 97%

Inappropriate trafficking of damaged mitochondria in Parkinson’s disease

Choong

Mochizuki

2017

Stem Cell Investig.

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“…The stabilization of Pink1 then appears to trigger a series of events that results in the degradation of these sick mitochondria. Pink1 is a kinase and when Pink1 is stabilized on dysfunctional mitochondria, it phosphorylates Miro, a protein that mediates kinesin dependent mitochondrial transport (S. Liu et al, 2012;Tsai et al, 2014;Wang et al, 2011). Further work indicates that phosphorylated Miro is degraded by Parkin, an E3 ubiquitin ligase that is activated by the E2 conjugase Ube2A/Rad6 in mammalian cells and in flies (Haddad et al, 2013).…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%