The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria
Wanting Xu, Lei Dong, Jiyan Dai, Lu Zhong, Xiao Ouyang, Jiaqian Li, Gaoqing Feng, Huahua Wang, Xuan Liu, Liying Zhou, Qin Xia
Abstract
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. This review highlights the UPS and autophagy-lysosome systems in degrading misfolded proteins, emphasizing substrate states, receptor oligomerization, and compartmentalization in cellular homeostasis. Innovatively links the coordination between the UPS and mitophagy to mitochondrial homeostasis by examining the interplay between mitochondrial dynamics and these degradation pathways to varying degrees of mitochondrial damage.