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Lysine 27 Ubiquitination of the Mitochondrial Transport Protein Miro Is Dependent on Serine 65 of the Parkin Ubiquitin Ligase

Birsa, N; Norkett, R; Wauer, T; Mevissen, TE; Wu, HC; Foltynie, T; Bhatia, K; ... Kittler, JT; + view all (2014) Lysine 27 Ubiquitination of the Mitochondrial Transport Protein Miro Is Dependent on Serine 65 of the Parkin Ubiquitin Ligase. J Biol Chem , 289 (21) pp. 14569-14582. 10.1074/jbc.M114.563031. Green open access

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Abstract

Mitochondrial transport plays an important role in matching mitochondrial distribution to localised energy production and calcium buffering requirements. Here we demonstrate that Miro1, an outer mitochondrial membrane (OMM) protein crucial for the regulation of mitochondrial trafficking and distribution, is a substrate of the PINK1/Parkin mitochondrial quality control system in human dopaminergic neuroblastoma cells. Moreover Miro1 turnover on damaged mitochondria is altered in Parkinson's disease (PD) patient derived fibroblasts containing a pathogenic mutation in the PARK2 gene (encoding Parkin). By analysing the kinetics of Miro1 ubiquitination we further demonstrate that mitochondrial damage triggers rapid (within minutes) and persistent K27 type ubiquitination of Miro1 on the OMM, dependent on PINK1 and Parkin. Proteasomal degradation of Miro1 is then seen on a slower timescale, within 2-3 hours of the onset of ubiquitination. We find Miro ubiquitination in dopaminergic neuroblastoma cells is independent of Miro1 phosphorylation at serine 156 (S156), but is dependent on the recently identified serine S65 residue within Parkin that is phosphorylated by PINK1. Interestingly we find that Miro1 can stabilise phospho-mutant versions of Parkin on the OMM, suggesting that Miro is also part of a Parkin receptor complex. Moreover, we demonstrate that S65 in Parkin is critical for regulating Miro levels upon mitochondrial damage in rodent cortical neurons. Our results provide new insights into the ubiquitination-dependent regulation of the Miro-mediated mitochondrial transport machinery by PINK1/Parkin and also suggest that disruption of this regulation may be implicated in PD pathogenesis.

Type: Article
Title: Lysine 27 Ubiquitination of the Mitochondrial Transport Protein Miro Is Dependent on Serine 65 of the Parkin Ubiquitin Ligase
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.M114.563031
Publisher version: http://dx.doi.org/10.1074/jbc.M114.563031
Language: English
Additional information: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License applies to Author Choice Articles
Keywords: Mitochondrial transport, Parkin, Parkinson's disease, Pink1, Ubiquitination, mitophagy
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1426266
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