MITOL promotes cell survival by degrading Parkin during mitophagy.
E3 ubiquitin ligase
MITOL/MARCH5
Parkin
mitochondria
mitophagy
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
03 03 2021
03 03 2021
Historique:
received:
19
08
2019
revised:
10
12
2020
accepted:
18
12
2020
pubmed:
11
2
2021
medline:
1
6
2021
entrez:
10
2
2021
Statut:
ppublish
Résumé
Parkin promotes cell survival by removing damaged mitochondria via mitophagy. However, although some studies have suggested that Parkin induces cell death, the regulatory mechanism underlying the dual role of Parkin remains unknown. Herein, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) regulates Parkin-mediated cell death through the FKBP38-dependent dynamic translocation from the mitochondria to the ER during mitophagy. Mechanistically, MITOL mediates ubiquitination of Parkin at lysine 220 residue, which promotes its proteasomal degradation, and thereby fine-tunes mitophagy by controlling the quantity of Parkin. Deletion of MITOL leads to accumulation of the phosphorylated active form of Parkin in the ER, resulting in FKBP38 degradation and enhanced cell death. Thus, we have shown that MITOL blocks Parkin-induced cell death, at least partially, by protecting FKBP38 from Parkin. Our findings unveil the regulation of the dual function of Parkin and provide a novel perspective on the pathogenesis of PD.
Identifiants
pubmed: 33565245
doi: 10.15252/embr.201949097
pmc: PMC7926225
doi:
Substances chimiques
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e49097Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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