Xu Wanting, Dong Lei, Dai Ji, Zhong Lu, Ouyang Xiao, Li Jiaqian, Feng Gaoqing, Wang Huahua, Liu Xuan, Zhou Liying, Xia Qin
State Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), Aerospace Center Hospital, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
Institute of International Technology and Economy, Development Research Center of the State Council, Beijing, 102208, China.
Cell Mol Life Sci. 2025 Jan 12;82(1):42. doi: 10.1007/s00018-024-05556-x.
Uncontrollable cancer cell growth is characterized by the maintenance of cellular homeostasis through the continuous accumulation of misfolded proteins and damaged organelles. This review delineates the roles of two complementary and synergistic degradation systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, in the degradation of misfolded proteins and damaged organelles for intracellular recycling. We emphasize the interconnected decision-making processes of degradation systems in maintaining cellular homeostasis, such as the biophysical state of substrates, receptor oligomerization potentials (e.g., p62), and compartmentalization capacities (e.g., membrane structures). Mitochondria, the cellular hubs for respiration and metabolism, are implicated in tumorigenesis. In the subsequent sections, we thoroughly examine the mechanisms of mitochondrial quality control (MQC) in preserving mitochondrial homeostasis in human cells. Notably, we explored the relationships between mitochondrial dynamics (fusion and fission) and various MQC processes-including the UPS, mitochondrial proteases, and mitophagy-in the context of mitochondrial repair and degradation pathways. Finally, we assessed the potential of targeting MQC (including UPS, mitochondrial molecular chaperones, mitochondrial proteases, mitochondrial dynamics, mitophagy and mitochondrial biogenesis) as cancer therapeutic strategies. Understanding the mechanisms underlying mitochondrial homeostasis may offer novel insights for future cancer therapies.
无法控制的癌细胞生长的特征是通过错误折叠的蛋白质和受损细胞器的持续积累来维持细胞内稳态。本综述阐述了两种互补且协同的降解系统，即泛素-蛋白酶体系统（UPS）和自噬-溶酶体系统，在错误折叠的蛋白质和受损细胞器降解以供细胞内循环利用方面的作用。我们强调了降解系统在维持细胞内稳态过程中相互关联的决策过程，例如底物的生物物理状态、受体寡聚化潜力（如p62）和区室化能力（如膜结构）。线粒体作为细胞呼吸和代谢的中心，与肿瘤发生有关。在随后的章节中，我们深入研究了线粒体质量控制（MQC）在维持人类细胞线粒体稳态中的机制。值得注意的是，我们在 mitochondrial repair and degradation pathways的背景下探讨了线粒体动力学（融合和裂变）与各种MQC过程（包括UPS、线粒体蛋白酶和线粒体自噬）之间的关系。最后，我们评估了将MQC（包括UPS、线粒体分子伴侣、线粒体蛋白酶、线粒体动力学、线粒体自噬和线粒体生物发生）作为癌症治疗策略的潜力。了解线粒体稳态的潜在机制可能为未来的癌症治疗提供新的见解。
