Ravindran Rishith, Gustafsson Åsa B
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
Nat Rev Cardiol. 2025 Mar 20. doi: 10.1038/s41569-025-01142-1.
Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy) or ejected from cells inside vesicles. The accumulation of dysfunctional mitochondria in cardiomyocytes is a hallmark of ageing and cardiovascular disease. This accumulation is driven by impaired mitochondrial quality control mechanisms and contributes to the development of heart failure. Therefore, there is a strong interest in developing therapies that directly target mitochondrial quality control in cardiomyocytes. In this Review, we discuss the current knowledge of the mechanisms involved in regulating mitochondrial quality in cardiomyocytes, how these pathways are altered with age and in disease, and the therapeutic potential of targeting mitochondrial quality control pathways in cardiovascular disease.
线粒体是多功能细胞器，对许多不同的细胞过程都很重要，包括能量产生以及脂肪酸、血红素和铁硫簇的生物合成。线粒体功能障碍会导致这些过程中断、过量活性氧的产生以及炎症和细胞死亡途径的激活。线粒体功能障碍的后果在心脏等能量需求旺盛的器官中尤其有害。终末分化心肌细胞的丧失会导致心脏重塑以及维持收缩能力的下降。因此，心肌细胞依赖多层线粒体质量控制机制来维持健康的线粒体群体。线粒体伴侣蛋白可防止蛋白质错误折叠和聚集，驻留蛋白酶通过蛋白水解作用清除受损蛋白质。无法修复的受损线粒体也可通过线粒体自噬（mitophagy）或从细胞内的囊泡中排出而被降解。心肌细胞中功能失调线粒体的积累是衰老和心血管疾病的一个标志。这种积累是由线粒体质量控制机制受损驱动的，并促进心力衰竭的发展。因此，人们对开发直接针对心肌细胞线粒体质量控制的疗法有着浓厚的兴趣。在本综述中，我们讨论了目前关于调节心肌细胞线粒体质量的机制的知识，这些途径在衰老和疾病中是如何改变的，以及针对心血管疾病中线粒体质量控制途径的治疗潜力。
