Cardiomyocyte Function and Trace Element (TE) Status during Aging: Role of Proteostasis

衰老过程中心肌细胞功能和微量元素 (TE) 状态：蛋白质稳态的作用

• 批准号: 448242516
• 负责人: Professor Dr. Tilman Grune
• 金额: --
• 依托单位: Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DIfE)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/448242516?language=en
• 关键词: Cardiomyocyte; Function; Trace; Element; TE

Iron (Fe) is essential for normal cellular functioning, but in excess, labile reactive Fe enhances oxidative stress, often resulting in a free radical-induced cell death. On the other hand, Fe is crucial for the energy production of cells, especially in cardiomyocytes possessing a high energy demand. In cardiomyocytes, Fe is also required for myoglobin function providing intracellular oxygen transport. Therefore, cardiomyocytes are highly vulnerable to disturbances of Fe metabolism. The functionality of the Fe metabolism is ensured by a number of proteins, which undergo a permanent turnover. Aging is characterized by malfunction of protein turnover, which is mainly due to reduced responses of the ubiquitin-proteasomal system and the autophagy-lysosomal system. This is a dominating process in aging and, therefore, a decline of proteostasis is a hallmark of the aging process. My group has been investigating the degradation of oxidatively modified proteins during aging, including the degradation of proteins of the Fe metabolism, and the regulation of redox-mediated protein degradation for several years. The goal of this project is to systematically investigate, how age-associated changes in proteostasis, in particular proteolytic pathways, effect trace element (TE) status and Fe metabolism-related proteins in cardiomyocytes in relation to cellular function. We will a) establish a correlation between proteolytic pathways and TE-binding and -regulating proteins in aging cardiomyocytes; b) test whether aging per se or hypertrophy as a known phenomenon of aging in cardiomyocytes is the driving factor for age-related TE (Fe) and functional disturbance; and c) test the interaction between various TE occurring during aging or inflammation and Fe metabolism. This will be done in the context with TE profiles of other organs and translated to the human situation.

铁 (Fe) 对于正常细胞功能至关重要，但过量的不稳定活性铁会增强氧化应激，常常导致自由基诱导的细胞死亡。另一方面，铁对于细胞的能量产生至关重要，特别是在能量需求较高的心肌细胞中。在心肌细胞中，肌红蛋白提供细胞内氧运输的功能也需要铁。因此，心肌细胞极易受到铁代谢紊乱的影响。铁代谢的功能是由许多蛋白质保证的，这些蛋白质会进行永久的更新。衰老的特点是蛋白质周转功能障碍，这主要是由于泛素-蛋白酶体系统和自噬-溶酶体系统的反应降低所致。这是衰老过程中的一个主导过程，因此，蛋白质稳态的下降是衰老过程的一个标志。我的小组多年来一直在研究衰老过程中氧化修饰蛋白质的降解，包括铁代谢的蛋白质降解，以及氧化还原介导的蛋白质降解的调节。该项目的目标是系统地研究与年龄相关的蛋白质稳态变化，特别是蛋白水解途径，如何影响心肌细胞中与细胞功能相关的微量元素（TE）状态和铁代谢相关蛋白质。我们将 a) 建立衰老心肌细胞中蛋白水解途径与 TE 结合和调节蛋白之间的相关性； b) 测试衰老本身或心肌细胞肥大（作为已知的心肌细胞衰老现象）是否是与年龄相关的 TE (Fe) 和功能障碍的驱动因素； c) 测试衰老或炎症过程中发生的各种 TE 与铁代谢之间的相互作用。这将在其他器官的 TE 概况的背景下完成，并转化为人类的情况。