TY  - JOUR
AU  - Baden, Pascale
AU  - Perez, Maria Jose
AU  - Raji, Hariam
AU  - Bertoli, Federico
AU  - Kalb, Stefanie
AU  - Illescas, María
AU  - Spanos, Fokion
AU  - Giuliano, Claudio
AU  - Calogero, Alessandra Maria
AU  - Oldrati, Marvin
AU  - Hebestreit, Hannah
AU  - Cappelletti, Graziella
AU  - Brockmann, Kathrin
AU  - Gasser, Thomas
AU  - Schapira, Anthony H V
AU  - Ugalde, Cristina
AU  - Deleidi, Michela
TI  - Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2023-00443
SP  - 1930
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Glucosylceramidase: genetics
KW  - Glucosylceramidase: metabolism
KW  - Proteomics
KW  - Parkinson Disease: metabolism
KW  - Mitochondria: genetics
KW  - Mitochondria: metabolism
KW  - Energy Metabolism: genetics
KW  - Mutation
KW  - Lysosomes: metabolism
KW  - alpha-Synuclein: metabolism
KW  - Mitochondrial Proteins: metabolism
KW  - ATP-Dependent Proteases: metabolism
KW  - Glucosylceramidase (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
KW  - LONP1 protein, human (NLM Chemicals)
KW  - Mitochondrial Proteins (NLM Chemicals)
KW  - ATP-Dependent Proteases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37024507
C2  - pmc:PMC10079970
DO  - DOI:10.1038/s41467-023-37454-4
UR  - https://pub.dzne.de/record/257563
ER  -