Letter | Published:

Daily magnesium fluxes regulate cellular timekeeping and energy balance

Nature volume 532, pages 375379 (21 April 2016) | Download Citation

Abstract

Circadian clocks are fundamental to the biology of most eukaryotes, coordinating behaviour and physiology to resonate with the environmental cycle of day and night through complex networks of clock-controlled genes1,2,3. A fundamental knowledge gap exists, however, between circadian gene expression cycles and the biochemical mechanisms that ultimately facilitate circadian regulation of cell biology4,5. Here we report circadian rhythms in the intracellular concentration of magnesium ions, [Mg2+]i, which act as a cell-autonomous timekeeping component to determine key clock properties both in a human cell line and in a unicellular alga that diverged from each other more than 1 billion years ago6. Given the essential role of Mg2+ as a cofactor for ATP, a functional consequence of [Mg2+]i oscillations is dynamic regulation of cellular energy expenditure over the daily cycle. Mechanistically, we find that these rhythms provide bilateral feedback linking rhythmic metabolism to clock-controlled gene expression. The global regulation of nucleotide triphosphate turnover by intracellular Mg2+ availability has potential to impact upon many of the cell’s more than 600 MgATP-dependent enzymes7 and every cellular system where MgNTP hydrolysis becomes rate limiting. Indeed, we find that circadian control of translation by mTOR8 is regulated through [Mg2+]i oscillations. It will now be important to identify which additional biological processes are subject to this form of regulation in tissues of multicellular organisms such as plants and humans, in the context of health and disease.

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Acknowledgements

G.v.O. is supported by a Royal Society University Research Fellowship (UF110173) and research grants (RS120372 and RS140275). J.S.O. is supported by the Medical Research Council (MC_UP_1201/4) and the Wellcome Trust (093734/Z/10/Z). M.P. is funded by KWF BUIT 2014-6637. L.F.L. and C.O.Y. are supported by Millennium Nucleus for Fungal Integrative and Synthetic Biology (NC120043), and Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT 1131030). S. K. Hodge is acknowledged for managing imaging facilities for algal experiments. At the MRC LMB, we are grateful to the Biomedical Services Group for animal care; M. Hastings and J. Chesham for supplying mouse tissue; P. Margiotta for assistance with figures. We also thank D. E. Salt, M. Knight, E. Grünewald, P. Crosby, L. Hewitt and B. Cross for criticism. The anti-puromycin ascites was a gift from M. Hegde.

Author information

Affiliations

  1. MRC Laboratory for Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK

    • Kevin A. Feeney
    • , Marrit Putker
    • , Nathaniel P. Hoyle
    •  & John S. O’Neill
  2. School of Biological Sciences, University of Edinburgh, Max Born Crescent, Edinburgh EH9 3BF, UK

    • Louise L. Hansen
    •  & Gerben van Ooijen
  3. Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile

    • Consuelo Olivares-Yañez
    •  & Luis F. Larrondo
  4. Department of Earth Sciences, University of Cambridge, Downing Street, Cambridge CB2 3EQ, UK

    • Jason Day
  5. School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, UK

    • Lorna J. Eades

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Contributions

G.v.O. and J.S.O. conceived the approach and designed the study. L.F.L. and C.O.Y. generated the Neurospora result. J.D. and L.E. performed ICP analyses. G.v.O. and L.L.H. performed Ostreococcus experiments. Human U2OS cell experiments were performed by K.A.F. M.P. performed mouse fibroblast experiments. N.P.H. provided analytical and intellectual contributions. G.v.O. and J.S.O. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to John S. O’Neill or Gerben van Ooijen.

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DOI

https://doi.org/10.1038/nature17407

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