%0 Journal Article
%A Baden, Pascale
%A Perez, Maria Jose
%A Raji, Hariam
%A Bertoli, Federico
%A Kalb, Stefanie
%A Illescas, María
%A Spanos, Fokion
%A Giuliano, Claudio
%A Calogero, Alessandra Maria
%A Oldrati, Marvin
%A Hebestreit, Hannah
%A Cappelletti, Graziella
%A Brockmann, Kathrin
%A Gasser, Thomas
%A Schapira, Anthony H V
%A Ugalde, Cristina
%A Deleidi, Michela
%T Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
%J Nature Communications
%V 14
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DZNE-2023-00443
%P 1930
%D 2023
%X 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.
%K Humans
%K Glucosylceramidase: genetics
%K Glucosylceramidase: metabolism
%K Proteomics
%K Parkinson Disease: metabolism
%K Mitochondria: genetics
%K Mitochondria: metabolism
%K Energy Metabolism: genetics
%K Mutation
%K Lysosomes: metabolism
%K alpha-Synuclein: metabolism
%K Mitochondrial Proteins: metabolism
%K ATP-Dependent Proteases: metabolism
%K Glucosylceramidase (NLM Chemicals)
%K alpha-Synuclein (NLM Chemicals)
%K LONP1 protein, human (NLM Chemicals)
%K Mitochondrial Proteins (NLM Chemicals)
%K ATP-Dependent Proteases (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37024507
%2 pmc:PMC10079970
%R 10.1038/s41467-023-37454-4
%U https://pub.dzne.de/record/257563