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

Pascale Baden, Maria Jose Perez, Hariam Raji, Federico Bertoli, Stefanie Kalb, María Illescas, Fokion Spanos, Claudio Giuliano, Alessandra Maria Calogero, Marvin Oldrati, Hannah Hebestreit, Graziella Cappelletti, Kathrin Brockmann, Thomas Gasser, Anthony H. V. Schapira, Cristina Ugalde and Michela Deleidi ()
Additional contact information
Pascale Baden: German Center for Neurodegenerative Diseases (DZNE)
Maria Jose Perez: German Center for Neurodegenerative Diseases (DZNE)
Hariam Raji: German Center for Neurodegenerative Diseases (DZNE)
Federico Bertoli: German Center for Neurodegenerative Diseases (DZNE)
Stefanie Kalb: German Center for Neurodegenerative Diseases (DZNE)
María Illescas: Instituto de Investigación Hospital 12 de Octubre (i + 12)
Fokion Spanos: German Center for Neurodegenerative Diseases (DZNE)
Claudio Giuliano: German Center for Neurodegenerative Diseases (DZNE)
Alessandra Maria Calogero: Università degli Studi di Milano
Marvin Oldrati: German Center for Neurodegenerative Diseases (DZNE)
Hannah Hebestreit: German Center for Neurodegenerative Diseases (DZNE)
Graziella Cappelletti: Università degli Studi di Milano
Kathrin Brockmann: German Center for Neurodegenerative Diseases (DZNE)
Thomas Gasser: German Center for Neurodegenerative Diseases (DZNE)
Anthony H. V. Schapira: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
Cristina Ugalde: Instituto de Investigación Hospital 12 de Octubre (i + 12)
Michela Deleidi: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-37454-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37454-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-37454-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().