Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism
Articolo
Data di Pubblicazione:
2023
Citazione:
Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism / P. Baden, M.J. Perez, H. Raji, F. Bertoli, S. Kalb, M. Illescas, F. Spanos, C. Giuliano, A.M. Calogero, M. Oldrati, H. Hebestreit, G. Cappelletti, K. Brockmann, T. Gasser, A.H.V. Schapira, C. Ugalde, M. Deleidi. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023 Dec), pp. 1930.1-1930.21. [10.1038/s41467-023-37454-4]
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.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
P. Baden, M.J. Perez, H. Raji, F. Bertoli, S. Kalb, M. Illescas, F. Spanos, C. Giuliano, A.M. Calogero, M. Oldrati, H. Hebestreit, G. Cappelletti, K. Brockmann, T. Gasser, A.H.V. Schapira, C. Ugalde, M. Deleidi
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