PINK1 and Parkin Target Miro for Phosphorylation and Degradation to Arrest Mitochondrial Motility

By Xinnan Wang, Dominic Winter, Ghazaleh Ashrafi, Julia S. Schlehe, Y. Wong, D. Selkoe, S. Rice, J. Steen, M. LaVoie, Thomas Schwarz. Cell, 2011

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SUMMARY Cells keep their energy balance and avoid oxidative stress by regulating mitochondrial movement, distribution, and clearance. We report here that two Parkinson’s disease proteins, the Ser/Thr-kinase PINK1 and ubiquitin-ligase Parkin, participate in this regulation by arresting mitochondrial movement. PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. Removal of Miro from the mitochondrion also detaches kinesin from its surface. By preventing mitochondrial movement, the PINK1/Parkin pathway may quarantine damaged mitochondria prior to their clearance. PINK1 has been shown to act upstream of Parkin but the mechanism corresponding to this relationship has not been known. We propose that PINK1 phosphorylation of substrates triggers the subsequent action of Parkin and the proteasome.

Subfields: Epidemiology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/7cccfdaac1d8440a81a3096039c60b26acc57199

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Citations in the corpus

Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. (2016, background): “Parkin further promotes segregation of damaged mitochondria by also tagging the mitochondrial transport protein Miro for degradation [35].”
Mitochondrial Dysfunction in Neurodegenerative Diseases (2012, background): “Moreover, there is evidence for a direct involvement of PINK1 and parkin in abnormal mitochondrial dynamics in fly, rat, and mouse models of PD (Wang et al., 2011; reviewed in Reddy et al., 2011).”
Synaptic energy use and supply. (2012, positive): “In Drosophila, presynaptic motor neuron terminals lacking functional mitochondria (because of Miro mutations that prevent kinesin-based transport) cannot sustain vesicle release during prolonged activity (Guo et al., 2005), because of a failure of myosin-drivenmobilisa- tion of reserve pool vesicles”
The pathways of mitophagy for quality control and clearance of mitochondria (2012, background): “Several proteins are now identified that are critical in directing autophagosomes to the mitochondria, including ATG32, Nix, p62, PINK1, and Parkin.”
Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control (2014, background): “…triggers whole-mitochondrial engulfment by autophagosomes and subsequent degradation through the autophagosome-lysosome pathway (a process known as mitophagy; Narendra et al, 2008; Geisler et al, 2010; Poole et al, 2010; Tanaka et al, 2010; Ziviani et al, 2010; Wang et al, 2011; Sun et al, 2012).”
Mitochondrial dynamics and mitochondrial quality control (2014, background): “Following Parkin-mediated ubiquitination of outer mitochondrial membrane proteins, the selective autophagy adapter protein p62/SQSTM1 (Sequestosome 1) is recruited to mitochondria and thought to play a role in mitophagy due to its capacity to directly interact with LC3 via its LC3 interacting…”
Mitochondria: In Sickness and in Health (2012, background): “We provide a current view of how mitochondrial functions impinge on health and disease.”
Defective Mitophagy in XPA via PARP1 Hyperactivation and NAD+/SIRT1 Reduction (2014, background): “Because PINK1 is retained at the outer mitochondrial membrane of depolarized mitochondria and XPA deficiency led to hyperpolarization of the membrane, we next investigated the stability of full-length PINK1 (Wang et al., 2011).”
PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 (2012, background): “GST-a-synuclein, GST-Parkin, GST-DJ1, GST-LRRK2 kinase inactive (KI) (1326-end D2017A), GST-Omi, GST-GAK KI (D191A), GST-FBX07, untagged VPS35 (GST cleaved), GST-TRAP1, GST-PARL, GST-NCS1 and GST-Miro2 were purified by similar methods except that recombinant GST-fusion proteins were affinity purifie”