학술논문
Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response.
Document Type
Article
Author
Source
Subject
*UBIQUITINATION
*UBIQUITIN ligases
*HOMEOSTASIS
*MITOCHONDRIAL proteins
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Language
ISSN
0261-4189
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. SYNOPSIS: Miro proteins are important regulators of initiation and progression of PINK1/Parkin‐dependent mitophagy upon mitochondrial damage. Long‐term disruption of mitochondrial homeostasis due to loss of Miro1 is associated with upregulation of the mitochondrial fusion machinery, remodelling of the mitochondrial network and sustained activation of the integrated stress response (ISR). Loss of Miro proteins is associated with delayed recruitment of E3 ubiquitin ligase Parkin to mitochondria upon organelle damage.Miro1 is ubiquitinated on multiple lysine residues.Miro1 ubiquitination and degradation are both required for mitophagy initiation and progression.Miro1 depletion in the mouse brain is associated with upregulation of the mitochondrial fusion machinery and mitochondrial remodelling.Long‐term disruption of mitochondrial homeostasis in Miro1 knockout brains is associated with hyperactivation of the ISR. [ABSTRACT FROM AUTHOR]