IMR Press / JIN / Volume 21 / Issue 5 / DOI: 10.31083/j.jin2105127
Open Access Original Research
Transcriptome Evidence Reveals Mitochondrial Unfolded Protein Response Participate in SH-SY5Y Cells Exposed to Manganese
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1 Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, 100069 Beijing, China
2 Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, 100069 Beijing, China
*Correspondence: (Jie Li); (Piye Niu)
These authors contributed equally.
Academic Editor: Yoshihiro Noda
J. Integr. Neurosci. 2022, 21(5), 127;
Submitted: 16 February 2022 | Revised: 11 March 2022 | Accepted: 14 March 2022 | Published: 21 July 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: Overexposure to manganese (Mn) can lead to neurodegenerative damage, resulting in manganism with similar syndromes to Parkinson’s disease (PD). However, little is known about changes in transcriptomics induced by the toxicological level of Mn. In this study, we conducted RNA-seq to explore the candidate genes and signaling pathways included by Mn in human SH-SY5Y neuroblastoma cells. Methods: The differentially expressed genes (DEGs) between the Mn-treated group and the control group were screened, and weighted gene co-expression network analysis (WGCNA) was employed to identify hub genes. Then, pathway enrichment analyses for those candidate genes were performed in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We further validated the concentration- and time-response effects of Mn exposure (0–500 μM, 3–12 h) on mitochondrial unfolded protein response (UPRMT) by real-time quantitative reverse transcription PCR (qRT-PCR). Results: The results showed 179 up-regulated differentially expressed genes (DEGs) and 681 down-regulated DEGs after Mn exposure. Based on the intersection of DEGs genes and hub genes, 73 DEGs were related to neurotoxicity. The comprehensive pathway analysis showed Mn had widespread effects on the mitogen-activated protein kinase (MAPK) signaling pathway, unfolded protein response, longevity regulating pathway, inflammatory bowel disease, and mitophagy signaling pathway. After Mn exposure, the expressions of activating transcription factor 3 (ATF3) and C-C motif chemokine ligand 2 (CCL2) increased, while the expressions of C/EBP homologous protein (CHOP), caseinolytic protease P (CLPP), and Lon protease 1 (LONP1) decreased in a concentration- and time-dependent manner. Conclusions: Overall, our study suggests that UPRMT is a new sight in understanding the mechanism of Mn-induced neurotoxicity.

candidate genes
mitochondrial unfolded protein response
Fig. 1.
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