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）对于正常的细胞功能至关重要，但在过量的，不稳定的反应性Fe会增强氧化应激，通常导致自由基诱导的细胞死亡。另一方面，FE对于细胞的能源产生至关重要，尤其是在具有高能量需求的心肌细胞中。在心肌细胞中，肌红蛋白功能也需要Fe，提供细胞内氧运输。因此，心肌细胞极易受到FE代谢障碍的影响。 FE代谢的功能由多种蛋白质确保，该蛋白会经历永久性营业额。衰老的特征在于蛋白质更新的故障，这主要是由于泛素 - 原始酶系统和自噬溶质体系统的反应减少所致。这是衰老中的一个主导过程，因此，蛋白质的下降是衰老过程的标志。我的小组一直在研究衰老过程中氧化修饰的蛋白质的降解，包括FE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已有几年了。该项目的目的是系统地研究蛋白质的蛋白质相关的变化，特别是蛋白水解途径，效应痕量元素（TE）状态（TE）状态和FE代谢相关的蛋白质在与细胞功能有关的心肌细胞中如何变化。我们将a）在衰老的心肌细胞中建立蛋白水解途径与蛋白质和调节蛋白之间的相关性； b）测试衰老本身还是肥大是心肌细胞衰老的已知现象是与年龄相关的TE（Fe）和功能性扰动的驱动因子； c）测试在衰老或炎症和Fe代谢过程中发生的各种TE的相互作用。这将在其他器官的特征中进行，并转化为人类状况。