Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 04 2023
06 04 2023
Historique:
received:
24
04
2022
accepted:
17
03
2023
medline:
10
4
2023
entrez:
6
4
2023
pubmed:
7
4
2023
Statut:
epublish
Résumé
Mutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.
Identifiants
pubmed: 37024507
doi: 10.1038/s41467-023-37454-4
pii: 10.1038/s41467-023-37454-4
pmc: PMC10079970
doi:
Substances chimiques
Glucosylceramidase
EC 3.2.1.45
alpha-Synuclein
0
LONP1 protein, human
EC 3.4.21.-
Mitochondrial Proteins
0
ATP-Dependent Proteases
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1930Informations de copyright
© 2023. The Author(s).
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