ClpP: A mitochondrial chaperone protease that helps cancer cells to escape ferroptosis through enhanced mitophagy
File(s)
Author(s)
Chang, Enqiang
Type
Thesis
Abstract
The Caseinolytic Mitochondrial Matrix Peptidase Proteolytic Subunit (ClpP) is crucial in maintaining mitochondrial homeostasis in cancer cells. Here, I combined The Cancer Genome Atlas (TCGA) databases, and proteomic analyses (proteomics) to identify critical associations between ClpP and cellular signalling pathways and to explore the involvement of reactive oxygen species (ROS), mitochondrial autophagy (mitophagy), and ferroptosis in clear cell renal cell carcinoma (ccRCC) cells. I demonstrated that ClpP promoted HIF-1α nuclear translocation and increased BCL2 Interacting Protein 3 (BNIP3), Microtubule Associated Protein 1 Light Chain 3 Alpha/Beta (LC3A/B), and Glutathione Peroxidase 4 (GPX4) expression but decreased Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) expression. Consequently, ClpP enhanced RCC cell malignancy by promoting BNIP3-LC3A/B-dependent mitophagy and compromising GPX4-mediated ferroptosis in both in vitro and xenograft models. ClpP inhibition led to mitochondrial dysfunction and attenuated RCC growth and survival. In addition, analyses of 431 patients with RCC revealed a positive correlation between ClpP expression and an unfavourable prognosis of the disease. Collectively, my findings highlight ClpP as a novel mediator in enhancing renal cancer malignancy through mitophagy-mediated decreased ferroptosis. In summary, while the development of ClpP inhibitors shows great promise for kidney cancers and potentially other cancers, further research is needed to fully understand the tissue-specific roles of ClpP and to design inhibitors that can effectively target cancer cells while sparing normal tissues.
Version
Open Access
Date Issued
2024-11-28
Date Awarded
2025-06-01
Copyright Statement
Attribution-Non Commercial-No Derivatives 4.0 International Licence (CC BY-NC-ND)
Advisor
Ma, Daqing
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)