Multi-Omics Analysis Reveals Distinct Lipid Remodelling and Mitochondrial Stress in SH-SY5Y Cells Modelling Parkinson’s Disease

<b>Background</b>: Neurotoxin-based in vitro models are commonly used to replicate the mitochondrial dysfunction and oxidative stress associated with Parkinson's disease (PD). While these models reproduce similar hallmark features of PD pathology, their capacity to capture lipid dysregulation remains less well defined. In particular, it is unclear whether different neurotoxins induce distinct glycerophospholipid (GPL) alterations that reflect upstream mechanisms driving mitochondrial impairment. <b>Methods</b>: We conducted a comparative multi-omics analysis in SH-SY5Y cells treated with either 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP⁺). Lipidomic profiling focused on GPL composition, while transcriptomic changes and organelle stress responses were assessed in parallel, including mitochondrial morphology and lipid droplet accumulation. <b>Results</b>: A total of 389 GPL species were identified. MPP⁺ suppressed the expression of mitochondrial genome-encoded respiratory genes and increased polyunsaturated 20:4 GPL species, while selectively depleting odd-chain lipids. In contrast, 6-OHDA activated pathways related to ferroptosis and endoplasmic reticulum stress, along with an accumulation of 20:3 enriched GPLs. In addition, GPL profiles in MPP⁺-treated cells showed a stronger similarity to previously reported alterations in PD patient brain tissue. Despite inducing some shared phenotypes such as lipid droplet accumulation and mitochondrial fragmentation, the two models displayed divergent molecular responses. <b>Conclusions</b>: Our findings reveal that MPP⁺ and 6-OHDA drive fundamentally different patterns of GPL remodelling and cellular stress. These results highlight lipid remodelling as a mechanistic indicator of neurotoxin-induced mitochondrial dysfunction and suggest that the MPP⁺ model may provide greater relevance for investigating GPL-related processes in PD.