Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
Pascale BadenMaria Jose PerezHariam RajiFederico BertoliStefanie KalbMaría IllescasFokion SpanosClaudio GiulianoAlessandra Maria CalogeroMarvin OldratiHannah HebestreitGraziella CappellettiKathrin BrockmannThomas GasserAnthony H V SchapiraCristina UgaldeMichela DeleidiPublished in: Nature communications (2023)
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.
Keyphrases
- quality control
- oxidative stress
- stem cells
- single cell
- cell death
- copy number
- diabetic rats
- reactive oxygen species
- heat stress
- gene expression
- high throughput
- mesenchymal stem cells
- bone marrow
- endoplasmic reticulum
- heat shock
- spinal cord
- replacement therapy
- drug delivery
- smoking cessation
- binding protein
- induced pluripotent stem cells
- amino acid