Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
Nat Commun
; 14(1): 1930, 2023 04 06.
Article
em En
| MEDLINE
| ID: mdl-37024507
ABSTRACT
Mutations in GBA1, the gene encoding the lysosomal enzyme ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Glucosilceramidase
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article