PT  - JOURNAL ARTICLE
AU  - Guillermo López-Doménech
AU  - Christian Covill-Cooke
AU  - Jack H. Howden
AU  - Nicol Birsa
AU  - Corinne Morfill
AU  - Nicholas J. Brandon
AU  - Josef T. Kittler
TI  - Miro ubiquitination is critical for efficient damage-induced PINK1/Parkin-mediated mitophagy
AID  - 10.1101/414664
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 414664
4099  - http://biorxiv.org/content/early/2018/09/11/414664.short
4100  - http://biorxiv.org/content/early/2018/09/11/414664.full
AB  - Clearance of mitochondria following damage is critical for neuronal homeostasis. Here, we investigate the role of Miro proteins in mitochondrial turnover by the PINK1 / Parkin mitochondrial quality control system in vitro and in vivo. We find that upon mitochondrial damage, Miro is promiscuously ubiquitinated on multiple lysine residues. Combined knockout of both Miro1 and Miro2 or block of Miro ubiquitination and subsequent degradation, lead to slowed mitophagy. In cultured neurons, Miro1 knockout also leads to delayed Parkin translocation onto damaged mitochondria and reduced mitochondrial clearance. In vivo, postnatal knockout of Miro1 in hippocampus and cortex disrupts mitophagy and leads to a dramatic age dependent upregulation of the mitofusin mitochondrial fusion machinery. Fluorescence imaging of aged neurons conditionally knocked out for Miro1 and expressing mitoDendra to label mitochondria in vivo, reveals that Mfn1 / Mfn2 upregulation leads to enlarged and hyperfused somatic mitochondria. Our results provide new insights into the role of Miro in PINK1/Parkin dependent mitophagy and further suggest that disruption of this regulation may be implicated in human neurological pathology.