UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response

López-Doménech, G; Howden, JH; Covill-Cooke, C; Morfill, C; Patel, JV; Bürli, R; Crowther, D; ... Kittler, JT; + view all (2021) Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response. The EMBO Journal , Article e100715. 10.15252/embj.2018100715. Green open access

[thumbnail of embj.2018100715.pdf]
Preview
Text
embj.2018100715.pdf - Published Version

Download (13MB) | Preview

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 the E3 ubiquitin ligase Parkin onto damaged mitochondria and reduced mitochondrial clearance in both fibroblasts and cultured neurons. Disrupted mitophagy in vivo, upon post-natal knockout of Miro1 in hippocampus and cortex, leads to a dramatic increase in mitofusin levels, the appearance of enlarged and hyperfused mitochondria and hyperactivation of the integrated stress response (ISR). Altogether, our results provide new insights into the central role of Miro1 in the regulation of mitochondrial homeostasis and further implicate Miro1 dysfunction in the pathogenesis of human neurodegenerative disease.

Type: Article
Title: Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.2018100715
Publisher version: https://doi.org/10.15252/embj.2018100715
Language: English
Additional information: Copyright © 2021 The Authors. Published under the terms of the CC BY 4.0 license.
Keywords: Parkinson’s disease, Rhot1, Rhot2, eIF2α, megamitochondria
UCL classification: UCL
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 > Department of Neuromuscular 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: https://discovery.ucl.ac.uk/id/eprint/10130424
Downloads since deposit
149Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item