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- W2591962181 abstract "Manganese (Mn) occurs naturally in the environment at low doses and is essential for normal cellular processes. Excessive occupational Mn exposure also causes oxidative stress and neurotoxicity with symptoms similar to Parkinsonism, creating an unusual requirement that Mn intake must be optimized to maintain homeostasis. We therefore employed a dose response design with human neuroblastoma SH-SY5Y cells to gain a mechanistic understanding of mitochondrial-cellular signaling networks generated in response to Mn varied over a physiologic to minimally toxicological range. We treated cells with different MnCl2 doses for 5h and found that cellular Mn accumulation was similar to literature values for human brain at ≤10 μM and increased to toxicological concentrations at ≥ 50 μM. Mn had dynamic effects on mitochondrial activity. Mn increased mitochondrial hydrogen peroxide (H2O2), antioxidant superoxide dismutase activity and oxidation of protein thiols in a dose dependent manner. In addition, we employed multi-omics approach (RMT- redox proteomics, metabolomics and transcriptomics) to identify central pathways of cell-mitochondrial oxidative signaling altered by Mn. Data analysis from multiple platforms including high resolution mass spectrometry-based metabolomics, transcriptomics by RNA-sequencing, and redox proteomics by redox isotope coded affinity tag-based mass spectrometry was performed. RMT results show that Mn significantly altered 100 protein peptides, 262 metabolites and 567 transcripts. Central RMT hubs altered by Mn include mitochondrial dysfunction, oxidative stress responses, energy metabolism, protein folding, cytoskeleton remodeling, tyrosine and butanoate metabolism. Together, we show that mitochondrial oxidative signaling and cellular neurotransmitter metabolism respond dynamically to different Mn levels. Such changes in the mitochondria could be critical determinants to complex cellular signaling that either protect or exacerbate the emergence of neurological disorders." @default.
- W2591962181 created "2017-03-16" @default.
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- W2591962181 date "2016-11-01" @default.
- W2591962181 modified "2023-09-22" @default.
- W2591962181 title "Integration of Multi-Omics Data Reveal Dynamic Oxidative Stress Responses to Manganese in Human SH-SY5Y Neuroblastoma Cells" @default.
- W2591962181 doi "https://doi.org/10.1016/j.freeradbiomed.2016.10.420" @default.
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