Circadian regulation of ion dynamics and ageing: implications for the rhythmic proteome.

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An endogenous clock organises organismal physiology and behaviour into 24-hour (circadian) rhythms, to accommodate the different physiological demands of day and night. The misalignment with the external time, as it occurs with jet lag or nightshift work is associated with an increased risk for diseases such as cancer and diabetes, and premature ageing. Each cell has its own clock, which confers circadian rhythmicity to several cellular processes from DNA replication and mitosis to protein synthesis and degradation. We found that Na+, K+, and, Cl- are rhythmically imported and exported across the plasma membrane to osmotically compensate for daily changes in cytosolic soluble protein abundance. This homeostatic control mechanism prevents the compensatory movement of water that would follow upon variation in macromolecule content and allows the cells to keep their volume constant. Importantly, we found that an intact ion transport system is required to accommodate new protein synthesis. In line with this, the manipulation of the intracellular ionic composition affects the activity of mTORC1, a protein complex that tunes cellular metabolism and growth to nutrient availability, thus preventing protein translation. In this proposal, we aim to further investigate the mechanisms by which the intracellular ionic composition regulates the mTORC1 signalling cascade and protein synthesis and how this remodels the circadian proteome. We will also analyse the contribution of osmolytes and amino acids to the buffering mechanism and how their (rhythmic) abundance links to mTORC1 activity and the partitioning between catabolic and anabolic processes. Finally, our preliminary data suggest that the intracellular abundance of several ions changes between young and old mice. Therefore, we aim to investigate how this osmotic buffering mechanism is affected by age and how this impacts the circadian proteome in vivo. Our findings will reveal fundamental mechanisms that link osmoregulation to mTORC1 activity and proteome remodelling and will have important implications for understanding the pathophysiology of many diseases caused by aberrant protein homeostasis, including ageing.