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Nat Struct Mol Biol. 2017 Jan;24(1):15-22. doi: 10.1038/nsmb.3331. Epub 2016 Nov 28.

Reciprocal regulation of carbon monoxide metabolism and the circadian clock.

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Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Institute of Pharmacology, Center for Cardiovascular Research CCR, Charité Universitätsmedizin Berlin, Berlin, Germany.
Bernhard-Nocht-Institut, Hamburg, Germany.
Department of Cell and Developmental Biology, University College London, London, UK.
Division of Biochemistry, Department of Biology, University of Fribourg, Fribourg, Switzerland.


Circadian clocks are cell-autonomous oscillators regulating daily rhythms in a wide range of physiological, metabolic and behavioral processes. Feedback of metabolic signals, such as redox state, NAD+/NADH and AMP/ADP ratios, or heme, modulate circadian rhythms and thereby optimize energy utilization across the 24-h cycle. We show that rhythmic heme degradation, which generates the signaling molecule carbon monoxide (CO), is required for normal circadian rhythms as well as circadian metabolic outputs. CO suppresses circadian transcription by attenuating CLOCK-BMAL1 binding to target promoters. Pharmacological inhibition or genetic depletion of CO-producing heme oxygenases abrogates normal daily cycles in mammalian cells and Drosophila. In mouse hepatocytes, suppression of CO production leads to a global upregulation of CLOCK-BMAL1-dependent circadian gene expression and dysregulated glucose metabolism. Together, our findings show that CO metabolism is an important link between the basic circadian-clock machinery, metabolism and behavior.

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