Objective: This study aimed to validate impairment of mitochondrial energetics and mitophagy in PD and the action of felodipine in restoring altered Mitochondria-lysosome (Mito-Lyso) homeostasis.

Background: Neurodegenerative diseases like Parkinson’s disease (PD) manifest with the neuronal accumulation of toxic proteins. Mito-Lyso contacts are recently identified sites for mediating normal mitochondrial functions, but their role in diseased human neurons remains unknown. GBA1 mutated PD cells exhibit impaired mitochondria-lysosome function due to decreased GBA1 (β-glucocerebrosidase (GCase) activity. Pharmacological agents that selectively modulate mitophagy are currently lacking. Thus, re-purposing of a well-tolerated drug can be the safest and effective therapeutic approach.

Method: Patient-derived primary skin fibroblasts of different GBA1 heterozygous PD and healthy controls were cultured under normal condition. Live cell confocal imaging (Zeiss LSM 980) based mitochondrial energetics (NAD/NADH assay) and investigation of Mitophagy (Mt-Keima and DQ-Red BSA Assay) were conducted. Optimum therapeutic dose of felodipine was established. Modulation of Mito-Lyso connections and mitophagy was further explored in felodipine treated and non-treated groups using live cell confocal imaging. Confocal microscopy images were analyzed using ImageJ and statistical analysis was performed using SPSS.

Results: TMRM based live cell imaging showed impaired mitochondrial energetics in GBA-1 mutated PD (p<0.05). Mt-Keima and DQ-Red BSA imaging validated impaired mitophagy and Mito-Lyso connections in GBA mutated PD cell lines compared to healthy controls (p 0.021). Apart from that mitochondrial dynamics was significantly dysregulated in PD cell lines (p<0.05). Felodipine treatment for 24h significantly corrected mitophagy and mitochondrial energetics in GBA-1 mutated PD cell lines(p<0.05).

Conclusion: Mitochondrial homeostasis and lysosome mediated mitophagy is critical to clear toxic proteins in neurodegenerations like PD. We have now validated impaired mitochondrial energetics and lysosome mediated mitophagy in GBA-1 mutated PD. Felodipine was effective in modulating Mito-Lyso connections and related mitophagy. Thus felodipine, a well-tolerated anti-hypertensive drug offers an opportunity for its re-purposing for PD therapeutics.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impaired-mitophagy-and-mitochondrial-energetics-in-parkinsons-disease-a-novel-therapeutic-strategy-of-re-tasking-felodipine/