Loss of neuronal Miro1 disrupts mitophagy and induces hyper-activation of the integrated stress response

ABSTRACT: 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. Genetic deletion of Miro or block of Miro1 ubiquitination and subsequent degradation lead to delayed translocation of E3 ubiquitin ligase Parkin onto damaged mitochondria and reduced mitochondrial clearance both in fibroblasts and cultured neurons. Disrupted mitophagy in vivo, upon postnatal knockout of Miro1 in hippocampus and cortex, leads to a dramatic increase in mitofusin levels, the appearance of enlarged and hyperfused mitochondria and hyperactivatio

SUBMITTER: Dr. Guillermo López-Doménech 

PROVIDER: S-SCDT-EMBOJ-2018-100715 | biostudies-other |

REPOSITORIES: biostudies-other