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

铁(Fe)对于正常的细胞功能是必不可少的，但过量的活性铁会增强氧化应激，通常会导致自由基诱导的细胞死亡。另一方面，铁对细胞的能量生产是至关重要的，特别是在具有高能量需求的心肌细胞中。在心肌细胞中，铁也是肌红蛋白提供细胞内氧气运输功能所必需的。因此，心肌细胞非常容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，这些蛋白质经历了永久的周转。衰老的特征是蛋白质代谢障碍，这主要是由于泛素-蛋白酶体系统和自噬-溶酶体系统的反应减弱所致。这是一个主导衰老的过程，因此，蛋白质平衡的下降是衰老过程的一个标志。几年来，我的团队一直在研究氧化修饰蛋白质在衰老过程中的降解，包括铁代谢蛋白质的降解，以及氧化还原介导的蛋白质降解的调节。该项目的目的是系统地研究与年龄相关的蛋白平衡的变化，特别是蛋白分解途径，如何影响心肌细胞中微量元素(TE)状态和铁代谢相关蛋白与细胞功能的关系。我们将a)在衰老的心肌细胞中建立蛋白分解途径与TE结合和调节蛋白之间的关系；b)检验衰老本身或肥大作为已知的心肌细胞衰老现象是否是年龄相关性TE(Fe)和功能障碍的驱动因素；以及c)测试在衰老或炎症过程中发生的各种TE与Fe代谢的相互作用。这将在其他器官的TE概况的背景下进行，并转化为人类情况。

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.