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.

Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism / P. Baden, M.J. Perez, H. Raji, F. Bertoli, S. Kalb, M. Illescas, F. Spanos, C. Giuliano, A.M. Calogero, M. Oldrati, H. Hebestreit, G. Cappelletti, K. Brockmann, T. Gasser, A.H.V. Schapira, C. Ugalde, M. Deleidi. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023 Dec), pp. 1930.1-1930.21. [10.1038/s41467-023-37454-4]

Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism

A.M. Calogero;G. Cappelletti;
2023

Abstract

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.
Settore BIO/16 - Anatomia Umana
dic-2023
6-apr-2023
Article (author)
File in questo prodotto:
File Dimensione Formato  
s41467-023-37454-4.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 9.14 MB
Formato Adobe PDF
9.14 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/975488
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 5
  • ???jsp.display-item.citation.isi??? ND
social impact