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Characteriration of mitochondrial stress response in Luhmes-derived dopaminergic neurons. Identification of open chromatin regions in stress and control conditions using ATACseq

ABSTRACT: Responsiveness of 6 days old differentiated Luhmes cells to mitochondrial stress induced by 8 hours treatment with Antimycin-A and Oligomycin analyzed by ATACseq. Enrichment analyses performed on genes associated with stress responsive ATACseq promoter regions validated the activation of transcriptional programs upon mitochondrial stress, in particular the engagement in the apoptotic pathway in response to ER stress as well as the alteration of neuronal identity

ORGANISM(S): Homo sapiens

PROVIDER: GSE272242 | GEO | 2026/07/31

REPOSITORIES: GEO

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Project description:To date, most in vitro toxicity testing has focused on acute effects of compounds at high concentrations. This testing strategy does not reflect real-life exposures, which might contribute to long-term disease outcome. We used a 3D-human dopaminergic in vitro LUHMES cell line model to determine whether effects of short-term rotenone exposure (100 nM, 24 h), are permanent or reversible. A decrease in complex I activity, ATP, mitochondrial diameter and neurite outgrowth were observed acutely. After compound removal, complex I activity was still inhibited, however, ATP levels were increased, cells were electrically active and aggregates restored neurite outgrowth integrity and mitochondrial morphology. We identified significant transcriptomic changes after 24 h which were not present 7 days after wash-out. Our results suggest that testing short-term exposures in vitro may capture many acute effects which cells can overcome, missing adaptive processes and long-term mechanisms. Additionally, to study cellular resilience, cells were re-exposed to rotenone after wash-out. Pre-exposed cells maintained higher metabolic activity than controls and presented a different expression pattern in genes previously shown to be altered by rotenone. NEF2L2, ATF4 and EAAC1 were downregulated upon single hit on day 15, but unchanged in pre-exposed aggregates. DAT and CASP3 were only altered after re-exposure to rotenone while TYMS and MLF1IP were downregulated in both single-exposed and pre-exposed aggregates. In summary, our study shows that a human cell-based 3D model can be used to assess cellular adaptation, resilience and long-term mechanisms relevant to neurodegenerative research. In this study acute and delayed effects of rotenone on transcriptome in 3D LUHMES were assessed by microarray. The goal was to characterize perturbations in gene expression immediately after exposure to rotenone and identify whether these perturbations persist after compound wash-out and recovery period

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Characteriration of mitochondrial stress response in Luhmes-derived dopaminergic neurons. Identification of open chromatin regions in stress and control conditions using ATACseq

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