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

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.

• Authors: 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, Michela Deleidi
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 1930 (04 06 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 37024507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Glucosylceramidase
• alpha-Synuclein
• LONP1 protein, human
• Mitochondrial Proteins
• ATP-Dependent Proteases

Topics

• Humans
• Glucosylceramidase (genetics, metabolism)
• Proteomics
• Parkinson Disease (metabolism)
• Mitochondria (genetics, metabolism)
• Energy Metabolism (genetics)
• Mutation
• Lysosomes (metabolism)
• alpha-Synuclein (metabolism)
• Mitochondrial Proteins (metabolism)
• ATP-Dependent Proteases (metabolism)