Abstract
Circadian (~24 h) rhythms are a fundamental feature of life, and their disruption increases the risk of infectious diseases, metabolic disorders, and cancer. We previously identified circadian oscillations in intracellular potassium concentrations in cells across kingdoms. Using highly divergent eukaryotic cell types, we now show that potassium levels act to regulate the period and phase of clock gene expression rhythms, therefore establishing intracellular potassium as a bona fide regulator of cellular circadian rhythms. Intracellular potassium also regulates critical events in the cell cycle. Strikingly, we observe that manipulating potassium levels inhibits cell proliferation in a circadian phase-dependent manner. As the timing of cell division is tuned by the circadian clock, we hypothesised that potassium rhythms could mechanistically link cell proliferation rhythms to the circadian cycle. In line with this hypothesis, we find that potassium levels are not only sufficient to instruct the timing of cell proliferation, but also essential to maintain coherent coupling between circadian rhythms and proliferation rhythms. These results establish circadian potassium rhythms as a primary factor coupling the cell- and circadian cycles in eukaryotic cells.
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Acknowledgments
The authors thank Erin Henslee and Fatima Labeed for expertise and equipment required for DEP measurements in Supplementary Fig. 1d. We also thank Seth Rubin for his critical review of early versions of the manuscript, Franck Delaunay for his kind gift of FUCCI-2A NIH 3T3 cells, and David Welsh for the generous donation of PERIOD2-LUCIFERASE mouse lung tissue. The attendees of the 2025 GRC Chronobiology are acknowledged for their input on Fig. 4g.
Funding
S.G.R., O.J.P.F., Y.P.C. and G.v.O. disclose support for the research of this work from the Wellcome Trust [225212/Z/22/Z]. S.G.R. and G.v.O. disclose support for the research of this work from the Leverhulme Trust [RPG−2019−184]. Y.P.C. and G.v.O. disclose support for the research of this work from the Biotechnology and Biological Sciences Research Council [APP3975]. P.C. discloses support for the research of this work from the Wellcome Trust Funder [320953/Z/24/Z], the Royal Society [RG\R1\251371] and a Chancellor’s Fellowship from the School of Biological Sciences, University of Edinburgh. P.C., R.K.S. and C.L.P. disclose support for the research of this work from the National Institutes of Health [R35 GM141849]. The UCSC Chemical Screening Center (RRID SCR_021114) and B.M.R. disclose support for the research of this work by an National Institutes of Health High End Instrumentation Grant [1S10OD028730-01A1]. C.P. discloses support for the research of this work by the Howard Hughes Medical Institute. A.S. discloses support for the research of this work by the Deutsche Forschungsgemeinschaft (DFG) under Germany’s Excellence Strategy EXC 2030 [390661388] and a project grant [510582209]. A.D.B. and J.S.O. disclose support for the research of this work by the Medical Research Council [MC_UP_1201/4] as part of United Kingdom Research and Innovation. L.L.H. and E.G. declare no relevant funding.
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Gil Rodríguez, S., Hansen, L.L., Fraser, O.J.P. et al. Intracellular potassium levels orchestrate circadian rhythmicity and cell division. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73351-2
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DOI: https://doi.org/10.1038/s41467-026-73351-2
