Exposure to rotenone triggers redox driven systemwide lipidome alterations and metabolic tradeoffs linked to Parkinsons disease
With the global rise in aging populations, the increasing incidence of neurodegenerative diseases underscores concerns about brain health, with pesticides like rotenone, emerging as key environmental hazardous. The precise mechanism by which chronic environmental concentration of rotenone exposure causes Parkinson-like phenotype is not understood. Previous studies showed that rotenone induces depletion of dopaminergic neurons by influencing mitochondrial functions. Mitochondrial dysfunction alters lipid homeostasis; therefore, brain lipids can be potential targets for the early risk assessment and prognosis of Parkinsons disease (PD). However, the specific lipidome changes and associated biomarkers of chronic rotenone in vivo exposure causing PD are largely unknown. This study investigates the lipid profile disruptions and biomarkers induced by environmentally relevant concentrations of chronic rotenone exposure using the neuro-model Drosophila melanogaster. An untargeted LC-HRAMS-based lipidomics identified that lipid classes, GP, SP, FA and GL were significantly altered. Furthermore, system-wide loss of cross talk of mitochondrial and peroxisome lipids by altering their redox homeostasis causing PD was observed. Additionally, lipid oxidative stress markers, and behavior abnormalities correlated with altered lipids linked to PD. The findings highlight the rotenone induced complex metabolic trade-offs, prioritizing brains neural integrity at the expense of peripheral lipid levels, leading to PD.