Targeting Lysosomal pH Restores Mitochondrial Quality Control in GBA1-Mutant Parkinson’s Disease

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Abstract Background Heterozygous mutations in the Glucocerebrosidase gene ( GBA1 ), which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are a genetic risk factor for Parkinson’s disease (PD), characterised by lysosomal dysfunction. The pathological effects of GBA1 mutations on PD, especially their influence on lysosomal function, mitophagy, and mitochondrial bioenergetics, remain unclear. Methods Fibroblasts and dopaminergic neurons, generated from induced pluripotent stem cells (iPSCs) derived from patients with GBA1-PD, were used in the study. Live-cell imaging was performed to assess lysosomal acidification, protease activity, mitochondrial membrane potential, and mitophagy. Mitochondrial cristae density and autophagic vesicles were examined using transmission electron microscopy. Oxygen consumption rate was measured by Seahorse assay. V-ATPase assembly was evaluated using FLIM-FRET, and pharmacological interventions included rapamycin and acidic nanoparticles. Statistical analyses involved unpaired t-tests, one-way ANOVA, and two-way ANOVA. Results GCase activity, lysosomal acidification, protease activity, mitophagy and mitochondrial bioenergetic function were all impaired. Mitochondria were fragmented, with reduced membrane potential and oxygen consumption. MTORC1 was constitutively phosphorylated and FLIM-FRET measurements confirmed impaired V-ATPase assembly, which was reversed following rapamycin treatment. Rapamycin and lysosome-specific acidic nanoparticles rescued lysosomal pH, restored mitophagy and mitochondrial membrane potential in GBA1 mutant dopaminergic neurons. Conclusions Our findings identify lysosomal acidification as the primary cause of impaired bioenergetic function and reduced mitophagy in GBA1-PD. MTORC1-mediated disruption of V-ATPase assembly drives these pathogenic processes. Pharmacological interventions that restore lysosomal pH—such as rapamycin or acidic nanoparticles—rescue both lysosomal and mitochondrial defects, offering a promising therapeutic approach for GBA1-PD.

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