Baden, Pascale;
Perez, Maria Jose;
Raji, Hariam;
Bertoli, Federico;
Kalb, Stefanie;
Illescas, María;
Spanos, Fokion;
... Deleidi, Michela; + view all
(2023)
Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
Nature Communications
, 14
(1)
, Article 1930. 10.1038/s41467-023-37454-4.
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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.
| Type: | Article |
|---|---|
| Title: | Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-023-37454-4 |
| Publisher version: | https://doi.org/10.1038/s41467-023-37454-4 |
| Language: | English |
| Additional information: | © 2023 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Humans, Glucosylceramidase, Proteomics, Parkinson Disease, Mitochondria, Energy Metabolism, Mutation, Lysosomes, alpha-Synuclein, Mitochondrial Proteins, ATP-Dependent Proteases |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10168626 |
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