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bioRxiv · 10.1101/2025.02.10.637453

Exposure to rotenone triggers redox driven systemwide lipidome alterations and metabolic tradeoffs linked to Parkinsons disease

Tiwari, A.·Rathor, P.·Patel, R. P.·Jha, P.·Birse, N.·CH, R.
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Abstract

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. Environmental implicationThis study highlights the environmental risks of chronic rotenone exposure, commonly used in agriculture. The findings show that even low concentrations of rotenone disrupt lipid metabolism, particularly in the brain, affecting mitochondrial and peroxisomal functions, contributing to depleting dopaminergic neurons, which are linked to neurodegenerative diseases like Parkinsons. The study also identify lipid markers linked to rotenone induced PD and reveals metabolic trade-offs, where the brain prioritizes neural integrity over peripheral lipid balance. These lipidome changes and redox-driven shifts threaten both individual health and ecosystem stability, emphasizing the need for policies to regulate pesticide use and minimize exposure risks. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/637453v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@145133aorg.highwire.dtl.DTLVardef@1f1612forg.highwire.dtl.DTLVardef@2360f0org.highwire.dtl.DTLVardef@b161f9_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

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Tiwari, A., Rathor, P., Patel, R. P., Jha, P., Birse, N., CH, R.. 2025-02-12. Exposure to rotenone triggers redox driven systemwide lipidome alterations and metabolic tradeoffs linked to Parkinsons disease. https://doi.org/10.1101/2025.02.10.637453

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