Mitochondrial dysfunction causes or contributes to a wide variety of pathologies, including neurodegenerative diseases, cancer, metabolic diseases, and aging. Cells actively surveil a number of mitochondrial readouts to ensure that cellular homeostasis is maintained. In this article, we characterize the role of the ethanol and stress response element (ESRE) pathway in mitochondrial surveillance and show that it is robustly activated when the concentration of reactive oxygen species (ROS) in the cell increases. While experiments were mostly performed in Caenorhabditis elegans, we observed similar gene activation profile in human cell lines. The linear relationship between ROS and ESRE activation differentiates ESRE from known mitochondrial surveillance pathways, such as the mitochondrial unfolded protein response (UPRmt), which monitor mitochondrial protein import. The ability of the ESRE network to be activated by increased ROS allows the cell to respond to oxidative and reductive stresses. The ESRE network works in tandem with other mitochondrial surveillance mechanisms as well, in a fashion that suggests a partially redundant hierarchy. For example, mutation of the UPRmt pathway results in earlier and more robust activation of the ESRE pathway. Interestingly, full expression of ATFS-1, a key transcription factor for the UPRmt, requires the presence of an ESRE motif in its promoter region. The ESRE pathway responds to mitochondrial damage by monitoring ROS levels. This response is conserved in humans. The ESRE pathway is activated earlier when other mitochondrial surveillance pathways are unavailable during mitochondrial crises, potentially to mitigate stress and restore health. However, the exact mechanisms of pathway activation and crosstalk remain to be elucidated. Ultimately, a better understanding of this network, and its role in the constellation of mitochondrial and cellular stress networks, will improve healthspan.

中文翻译：

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ROS和线粒体损伤激活了进化保守的ESRE应激反应网络。

线粒体功能障碍导致或促成多种病理，包括神经退行性疾病，癌症，代谢性疾病和衰老。细胞积极监测许多线粒体读数，以确保维持细胞稳态。在本文中，我们表征了乙醇和应激反应元件（ESRE）途径在线粒体监测中的作用，并表明当细胞中活性氧（ROS）浓度增加时，乙醇和应激反应元件（ESRE）途径会被稳定激活。虽然大部分实验都是在秀丽隐杆线虫中进行的，但我们在人类细胞系中观察到了相似的基因激活模式。ROS和ESRE激活之间的线性关系使ESRE与已知的线粒体监测途径（例如线粒体未折叠蛋白反应（UPRmt））区别开来，监测线粒体蛋白质的进口。ESRE网络被增加的ROS激活的能力使细胞能够对氧化和还原压力做出反应。ESRE网络还与其他线粒体监视机制协同工作，其方式暗示了部分冗余的层次结构。例如，UPRmt途径的突变导致ESRE途径的更早和更牢固的激活。有趣的是，ATFS-1（UPRmt的关键转录因子）的完整表达需要在其启动子区域存在ESRE基序。ESRE途径通过监测ROS水平来响应线粒体损伤。这种反应在人类中是保守的。当线粒体危机期间无法使用其他线粒体监测途径时，ESRE途径会更早被激活，潜在地减轻压力并恢复健康。但是，途径激活和串扰的确切机制仍有待阐明。最终，更好地了解该网络及其在线粒体和细胞应激网络群中的作用，将改善健康状况。