Daily magnesium fluxes regulate cellular timekeeping and energy balance

Abstract

Circadian clocks are fundamental to the biology of most eukaryotes, coordinating behavior and physiology to resonate with the environmental cycle of day and night through complex networks of clock-controlled genes1-3. 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, [Mg 2+ ] i , which act as a cell-autonomous timekeeping component to determine key clock properties in both a human cell line and a unicellular alga that diverged from metazoans more than 1 billion years ago6. Given the essential role of Mg 2+ as a cofactor for ATP, a functional consequence of [Mg 2+ ] 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 Mg 2+ availability has potential to impact upon many of the cell's >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 [Mg 2+ ] i oscillations. It will now be important to identify which additional biological # To whom correspondence should be sent: Gerben.vanOoijen@ed.ac.uk, oneillj@mrc-lmb.cam.ac.uk. Author contributions GvO and JSO conceived the approach and designed the study. LFL and COY generated the Neurospora result. JD and LE performed ICP analyses. GvO and LLH performed Ostreococcus experiments. Human U2OS cell experiments were performed by KAF. MP performed mouse fibroblast experiments. NPH provided analytical and intellectual contributions. GvO and JSO wrote the manuscript.

PRL2 links magnesium flux and sex-dependent circadian metabolic rhythms

“…Recently, Feeney et al reported a novel physiological function for Mg 2+ in cellular circadian regulation. Namely, they observed that rhythmic changes of intracellular Mg 2+ concentration regulated cellular timekeeping and energy balance (4). This finding shed light on the importance of rhythmic Mg 2+ levels on circadian regulation of cellular energy metabolism (5).…”

Intracellular magnesium and the rhythms of life

“…In a recent publication in Nature, 1 Older observations have reported circadian [Mg 2C ] i rhythms in whole organisms, and our findings therefore provide a cellular basis for understanding this earlier work. For example, as early as 1978, Kondo et al showed that magnesium and potassium ions disappear from media in which duckweed is grown with a »24-hour rhythm.…”

“…2 Uptake rhythms were not observed for calcium, closely mirroring our recent observation of intracellular oscillations in magnesium, potassium but not calcium in representatives of 3 eukaryotic kingdoms. 1 Similar to intracellular ionic oscillations, uptake rhythms were temperature compensated and entrained by light/dark cycles. 3 It seems reasonable therefore to assume that whole-organism uptake rhythms reflect the summation of individual cellular oscillations.…”

“…at least partly due to the unusually high magnesium sensitivity of mTOR. 1 It is enticing to speculate on future applications for safer shift work or more comfortable intercontinental travel, but essential to remain cautious and realistic, as our knowledge is very much incomplete even at the cellular level. What is most apparent however, is that a full understanding of the dynamic regulation of metabolism via magnesium across different eukaryotes and timescales would unveil a huge number of potential applications throughout major areas of contemporary challenges to human societies, such as human metabolic health, food crop yields, and the productivity of microbial biotechnology.…”

Yes, circadian rhythms actually do affect almost everything

“…As we (as a field) dig more deeply into these steps, it is more and more apparent that each step confers its own brand of regulation, but the aspect discovered by Feeney et al [1] is particularly pervasive and therefore demands attention.…”