Journal
REDOX BIOLOGY
Volume 24, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2019.101194
Keywords
Adaptive homeostasis; Hyperoxia; Nrf2; 20S proteasome; Immunoproteasome; NQ01; Bachl; c-Myc; Lon protease; OXR1
Categories
Funding
- USA National Science Foundation [DGE-1418060]
- NIH grant from the National Institute of Environmental Health Sciences of the US National Institutes of Health [ES003598]
- NIH grant from the National Institute of General Medical Sciences of the National Institutes of Health [Fi2GM123963]
- National Institute of Environmental Health Sciences of the US National Institutes of Health [ES003598]
- National Institute on Aging of the US National Institutes of Health [AG052374]
- National Institute of Environmental Health Sciences [ES023864]
- Rose Hills USC Summer Research Scholarship
- MRC [MC_EX_MR/P502005/1] Funding Source: UKRI
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The Nrf2 signal transduction pathway plays a major role in adaptive responses to oxidative stress and in maintaining adaptive homeostasis, yet Nrf2 signaling undergoes a significant age-dependent decline that is still poorly understood. We used mouse embryonic fibroblasts (MEFs) cultured under hyperoxic conditions of 40% O-2, as a model of accelerated ageing. Hyperoxia increased baseline levels of Nrf2 and multiple transcriptional targets (20S Proteasome, Immunoproteasome, Lon protease, NQO1, and HO-1), but resulted in loss of cellular ability to adapt to signaling levels (1.0 mu M) of H2O2. In contrast, MEFs cultured at physiologically relevant conditions of 5% O-2 exhibited a transient induction of Nrf2 Phase II target genes and stress-protective enzymes (the Lon protease and OXR1) following H2O2 treatment. Importantly, all of these effects have been seen in older cells and organisms. Levels of Two major Nrf2 inhibitors, Bach1 and c-Myc, were strongly elevated by hyperoxia and appeared to exert a ceiling on Nrf2 signaling. Bach1 and c-Myc also increase during ageing and may thus be the mechanism by which adaptive homeostasis is compromised with age.
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