Birsa, N; (2015) Mitochondrial transport regulation in Parkinson’s disease. Doctoral thesis , UCL (University College London).

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Abstract

Mitochondrial transport plays an important role in matching mitochondrial distribution to localised energy production and calcium buffering requirements. Miro is an outer mitochondrial membrane (OMM) protein that, via its interaction with the kinesin motors, mediates mitochondrial trafficking along the cytoskeletal tracks. Mitochondria, however, not only need to be delivered to specific cellular sites, but also need to be retrieved when not functional. PINK1 and Parkin are two Parkinson’s disease (PD)-associated proteins that work in concert in a mitochondrial quality control system. PINK1 is a mitochondrial serine-threonine kinase generally present at low levels on the OMM. PINK1 selectively accumulates on the OMM of damaged mitochondria, and recruits Parkin, a cytosolic E3 ubiquitin ligase from the cytosol. Parkin then ubiquitinates several substrates on the OMM, leading to the initiation of mitophagy. In this thesis Miro1 is shown to be a substrate of the PINK1/Parkin pathway in human dopaminergic neuroblastoma cells. Analysis of the kinetics of Miro1 ubiquitination, further demonstrates that mitochondrial damage triggers rapid K27-type ubiquitination of Miro1 on the OMM, dependent on PINK1 and Parkin. Proteasomal degradation of Miro1 is then seen on a slower timescale. Miro1 ubiquitination in dopaminergic neuroblastoma cells is found to be independent of Miro1 phosphorylation at serine 156, but dependent on the recently identified serine 65 residue within Parkin that is phosphorylated by PINK1. Interestingly, Miro1 can stabilise phospho-mutant versions of Parkin on the OMM, suggesting that Miro is also part of a Parkin receptor complex. These 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.

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