Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice

Clara Bien, Alison H. Affinati, Kathryn M Ramsey, Hsin Yu Kuo, Wei Yu, Laura A. Sena, Olga Ilkayeva, Biliana Marcheva, Yumiko Kobayashi, Chiaki Omura, Daniel C. Levine, David J. Bacsik, David R Gius, Christopher B. Newgard, Eric Goetzman, Navdeep Chandel, John M. Denu, Milan Mrksich, Joseph Bass*

*Corresponding author for this work

Research output: Contribution to journalArticle

329 Scopus citations


Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD+) biosynthesis, adenosine triphosphate production, and mitochondrial respiration through modulation of mitochondrial protein acetylation to synchronize oxidative metabolic pathways with the 24-hour fasting and feeding cycle. Circadian control of the activity of the NAD +-dependent deacetylase sirtuin 3 (SIRT3) generated rhythms in the acetylation and activity of oxidative enzymes and respiration in isolated mitochondria, and NAD+ supplementation restored protein deacetylation and enhanced oxygen consumption in circadian mutant mice. Thus, circadian control of NAD+ bioavailability modulates mitochondrial oxidative function and organismal metabolism across the daily cycles of fasting and feeding.

Original languageEnglish (US)
Article number1243417
Issue number6158
StatePublished - Jan 1 2013

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    Bien, C., Affinati, A. H., Ramsey, K. M., Kuo, H. Y., Yu, W., Sena, L. A., Ilkayeva, O., Marcheva, B., Kobayashi, Y., Omura, C., Levine, D. C., Bacsik, D. J., Gius, D. R., Newgard, C. B., Goetzman, E., Chandel, N., Denu, J. M., Mrksich, M., & Bass, J. (2013). Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science, 342(6158), [1243417].