The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria

Wanting Xu, Lei Dong, Ji Dai, Lu Zhong, Xiao Ouyang, Jiaqian Li, Gaoqing Feng, Huahua Wang, Xuan Liu, Liying Zhou, Qin Xia*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish
Article number42
JournalCellular and Molecular Life Sciences
Volume82
Issue number1
DOIs
Publication statusPublished - Dec 2025

Keywords

  • Autophagy-lysosome
  • Cancer therapy
  • Mitochondrial chaperones
  • Mitochondrial proteases
  • Mitophagy
  • Protein quality control
  • UPS

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Xu, W., Dong, L., Dai, J., Zhong, L., Ouyang, X., Li, J., Feng, G., Wang, H., Liu, X., Zhou, L., & Xia, Q. (2025). The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria. Cellular and Molecular Life Sciences, 82(1), Article 42. https://doi.org/10.1007/s00018-024-05556-x