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Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.

ABSTRACT: Cancer cells depend on mitochondrial reprogramming for growth, but this raises reactive oxygen species (ROS), increasing reliance on protein quality control (PQC) repair mechanisms. The mitochondrial proteome is maintained through a robust PQC composed of chaperones and proteases, including the mitochondrial matrix protease caseinolytic protease P (ClpP). ClpP has recently emerged as a potential therapeutic target against cancer. Notably, imipridones act as ClpP agonists and have shown potent anticancer activity by inhibiting mitochondrial Electron Transport Chain (ETC) function. In this study, we developed a new generation ClpP agonist, compound 9 (MS6076), which exhibits enhanced ClpP binding, more potent disruption of mitochondrial ETC and lethality in breast cancer models compared to the imipridone ONC212. Furthermore, we show that compound 9 induced cell death in cancer cells resistant to ONC212. The discovery and characterization of compound 9 therefore add to the expanding arsenal of imipridones to target ClpP in cancer.

SUBMITTER: Xu Z

PROVIDER: S-EPMC12700136 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature

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Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.

Xu Zhongli Z Pokushalov Dmitry D Kabir Md M Lee Youngeun Y Chattopadhyay Mrittika M Jenkins Edmund C EC Choo Cessarina C Kaniskan H Ümit HÜ Germain Doris D Jin Jian J

Journal of medicinal chemistry 20251001 20

Cancer cells depend on mitochondrial reprogramming for growth, but this raises reactive oxygen species (ROS), increasing reliance on protein quality control (PQC) repair mechanisms. The mitochondrial proteome is maintained through a robust PQC composed of chaperones and proteases, including the mitochondrial matrix protease caseinolytic protease P (ClpP). ClpP has recently emerged as a potential therapeutic target against cancer. Notably, imipridones act as ClpP agonists and have shown potent an ...[more]

PMID: 41032690

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Project description:The peptidase ClpP is conserved from bacteria to human. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder. Because of its known relevance for the mitochondrial unfolded protein response during cell stress, we characterized two ClpP knock-out mouse founder lines and documented similar phenotypes. Ubiquitously, ClpP absence led to accumulation of its interactor protein ClpX without transcript upregulation. Interestingly, most wild-type tissues with substantial ClpP amounts had no detectable ClpX. This inverse correlation suggests that ClpX levels and degradation are regulated by ClpP. The expectation of similar protein levels, in view of a reported association of heptameric ClpP rings with hexameric ClpX rings, was confirmed only in testis of wild-type animals. Germline tissue was exceptional also in its vulnerability to ClpP deletion, with both founder lines showing complete infertility for males and females. Otherwise, ubiquitous mitochondrial dysfunction was apparent from severe growth retardation and reduced spontaneous motor activity of the animals, and from a pronounced decrease in pre-/postnatal survival. Spermatogenesis was found aborted at the spermatid stage, acrosomes and axonemes were not formed. Overall, tissue-specific roles of ClpP were evident by this massive effect for germ cells, mild bioenergetic deficits in muscle and liver tissues, and excellent compensation in brain. ClpX was previously reported to chaperone unfolded proteins and also DNA condensation in mitochondria, so it is likely that this pathway is particularly susceptible in germ cells. In conclusion, our study indicates that the role of ClpP in quality control is indispensable during development for cells with rapid changes of mitochondrial numbers, and is relevant during aging for growth and survival of the organism. Factorial design comparing ClpP knock-out mice with wild type littermates in five different tissues (brain, testis, liver, skeletal and heart muscle)

Dataset Information

Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.

Publications

Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.

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