Mammalian Circadian Period, But Not Phase and Amplitude, Is Robust Against Redox and Metabolic Perturbations

Antioxidants & Redox Signaling
Marrit PutkerJohn S O'Neill

Abstract

Circadian rhythms permeate all levels of biology to temporally regulate cell and whole-body physiology, although the cell-autonomous mechanism that confers ∼24-h periodicity is incompletely understood. Reports describing circadian oscillations of over-oxidized peroxiredoxin abundance have suggested that redox signaling plays an important role in the timekeeping mechanism. Here, we tested the functional contribution that redox state and primary metabolism make to mammalian cellular timekeeping. We found a circadian rhythm in flux through primary glucose metabolic pathways, indicating rhythmic NAD(P)H production. Using pharmacological and genetic perturbations, however, we found that timekeeping was insensitive to changes in glycolytic flux, whereas oxidative pentose phosphate pathway (PPP) inhibition and other chronic redox stressors primarily affected circadian gene expression amplitude, not periodicity. Finally, acute changes in redox state decreased PER2 protein stability, phase dependently, to alter the subsequent phase of oscillation. Circadian rhythms in primary cellular metabolism and redox state have been proposed to play a role in the cellular timekeeping mechanism. We present experimental data testing that hypothesis. ...Continue Reading

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Citations

Oct 1, 2018·The European Journal of Neuroscience·Yukihiro Yamada, Rebecca A Prosser
Apr 19, 2018·EMBO Molecular Medicine·T Katherine TamaiTakashi Yoshimura
Nov 10, 2017·Science Translational Medicine·Nathaniel P HoyleJohn S O'Neill
May 18, 2019·Current Pharmaceutical Design·Colleen Marie Bartman, Tobias Eckle
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Feb 12, 2021·Frontiers in Neuroscience·Rezwana AhmedYasumasa Bessho
Mar 10, 2021·Nature Chemical Biology·John S O'Neill
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Santiago Andrés PlanoJuan José Chiesa

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Methods Mentioned

BETA
nuclear translocation
transfection
glycosylation

Software Mentioned

FIJI
XCalibur Quan Browser
XCalibur Qual Browser

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