Home > Publications Database > Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism. > print

001     257563
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024 7 _ |a 10.1038/s41467-023-37454-4
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100 1 _ |a Baden, Pascale
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245 _ _ |a Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
260 _ _ |a [London]
|c 2023
|b Nature Publishing Group UK
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520 _ _ |a 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.
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650 _ 7 |a Glucosylceramidase
|0 EC 3.2.1.45
|2 NLM Chemicals
650 _ 7 |a alpha-Synuclein
|2 NLM Chemicals
650 _ 7 |a LONP1 protein, human
|0 EC 3.4.21.-
|2 NLM Chemicals
650 _ 7 |a Mitochondrial Proteins
|2 NLM Chemicals
650 _ 7 |a ATP-Dependent Proteases
|0 EC 3.4.21.-
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Glucosylceramidase: genetics
|2 MeSH
650 _ 2 |a Glucosylceramidase: metabolism
|2 MeSH
650 _ 2 |a Proteomics
|2 MeSH
650 _ 2 |a Parkinson Disease: metabolism
|2 MeSH
650 _ 2 |a Mitochondria: genetics
|2 MeSH
650 _ 2 |a Mitochondria: metabolism
|2 MeSH
650 _ 2 |a Energy Metabolism: genetics
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Lysosomes: metabolism
|2 MeSH
650 _ 2 |a alpha-Synuclein: metabolism
|2 MeSH
650 _ 2 |a Mitochondrial Proteins: metabolism
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650 _ 2 |a ATP-Dependent Proteases: metabolism
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700 1 _ |a Perez, Maria Jose
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700 1 _ |a Raji, Hariam
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700 1 _ |a Bertoli, Federico
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700 1 _ |a Kalb, Stefanie
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700 1 _ |a Illescas, María
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700 1 _ |a Spanos, Fokion
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700 1 _ |a Giuliano, Claudio
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700 1 _ |a Calogero, Alessandra Maria
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700 1 _ |a Oldrati, Marvin
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700 1 _ |a Hebestreit, Hannah
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700 1 _ |a Cappelletti, Graziella
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700 1 _ |a Brockmann, Kathrin
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700 1 _ |a Gasser, Thomas
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700 1 _ |a Schapira, Anthony H V
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700 1 _ |a Ugalde, Cristina
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700 1 _ |a Deleidi, Michela
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773 _ _ |a 10.1038/s41467-023-37454-4
|g Vol. 14, no. 1, p. 1930
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|t Nature Communications
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856 4 _ |y OpenAccess
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