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

离子动力学和衰老的昼夜节律调节：对节律蛋白质组的影响。

• 批准号: 510582209
• 负责人: Dr. Alessandra Stangherlin
• 金额: --
• 依托单位: Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/510582209?language=en
• 关键词: Circadian; regulation; ion; dynamics; ageing

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.

内源性生物钟将生物体的生理和行为组织成24小时（昼夜）节律，以适应白天和黑夜的不同生理需求。时差或夜班工作与外部时间不一致，与癌症和糖尿病等疾病的风险增加以及过早衰老有关。每个细胞都有自己的时钟，它赋予从DNA复制和有丝分裂到蛋白质合成和降解的几个细胞过程昼夜节律。我们发现，Na+，K+，和，Cl-有节奏地进口和出口的质膜，以补偿细胞溶质可溶性蛋白丰度的日常变化。这种稳态控制机制防止了大分子含量变化后水的补偿运动，并允许细胞保持其体积恒定。重要的是，我们发现，一个完整的离子转运系统是必需的，以适应新的蛋白质合成。与此一致，细胞内离子组成的操纵影响mTORC 1的活性，mTORC 1是一种蛋白质复合物，可调节细胞代谢和生长以获得营养，从而阻止蛋白质翻译。在这个提议中，我们的目标是进一步研究细胞内离子组成调节mTORC 1信号级联和蛋白质合成的机制，以及如何重塑昼夜蛋白质组。我们还将分析渗透调节剂和氨基酸对缓冲机制的贡献，以及它们的（节律性）丰度如何与mTORC 1活性以及分解代谢和合成代谢过程之间的分配联系起来。最后，我们的初步数据表明，几种离子的细胞内丰度的变化之间的年轻和老年小鼠。因此，我们的目的是研究这种渗透缓冲机制是如何受到年龄的影响，以及这如何影响体内的昼夜蛋白质组。我们的研究结果将揭示mTORC 1活性和蛋白质组重构的基本机制，并将对理解异常蛋白质稳态引起的许多疾病的病理生理学具有重要意义，包括衰老。