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Molecular Alterations in Mitochondrial Deficient Neuronal Cell Models
Menta, Blaise W.
Menta, Blaise W.
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Abstract
Mitochondrial dysfunction is increasingly recognized as a pivotal player in Alzheimer's disease (AD) pathology. This study delves into the role of mitochondrial DNA (mtDNA) depletion in two neuronal cell lines, SH-SY5Y and NT2 ρ0, to mimic the chronic mitochondrial stress observed in AD. Through comprehensive analyses of transcriptomes, proteomes, and lipidomes, we uncover significant cellular responses that mirror the complex molecular landscape of AD. Differential gene expression analysis reveals a significant overlap between the cell lines, indicating a uniform response to mitochondrial dysfunction alongside unique cell-specific reactions. Gene Set Enrichment Analysis (GSEA) highlights an adaptive response in SY5Y cells with enrichment in pathways related to protein synthesis, while NT2 ρ0 cells exhibit a more targeted response affecting neuronal functions. The study underscores the critical roles of NET1 signaling and axon guidance in neuronal health, with downregulation of NET1 paralleling trends observed in mild cognitive impairment (MCI) and AD. Pathway analyses further reveal the importance of neuronal systems and G Protein-Coupled Receptor (GPCR) signaling in AD pathology. Our findings also indicate a multifaceted cellular response to mitochondrial stress, as evidenced by changes in RNA processing, microtubule-based processes, and lipid metabolism, with notable alterations in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and polyunsaturated fatty acid (PUFA) levels. The study's Expression Change Index (ECI) and Over-Representation Analysis (ORA) using the KEGG database identify disrupted pathways closely linked to neurological disorders, particularly AD. This research elucidates the intricate relationship between mitochondrial dysfunction and neuronal/synaptic functions, providing fresh insights into AD's transcriptomic and lipidomic alterations. By highlighting the differential pathway enrichment in SY5Y and NT2 ρ0 cells, our study contributes to a deeper understanding of AD's unique cellular and synaptic architectures, suggesting that AD pathology may involve extensive networks of interacting proteins beyond isolated protein changes. These findings enhance our comprehension of AD pathology and lay the groundwork for future investigations into the diverse impacts of mitochondrial dysfunction on neurobiology, potentially paving the way for novel therapeutic strategies for AD and related neurodegenerative diseases.
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Date
2024-05-31
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University of Kansas
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This item contains archived web content.
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Available after 5/31/2028
Adobe PDF, 26.32 MB
- Embargoed until 2028-05-31
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Keywords
Neurosciences, Alzheimer's disease, Brain, Lipids, Mitochondria, Neurodegeneration, Transcriptomic