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Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.

ABSTRACT: The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.

SUBMITTER: Ishizawa J

PROVIDER: S-EPMC6620028 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.

Ishizawa Jo J Zarabi Sarah F SF Davis R Eric RE Halgas Ondrej O Nii Takenobu T Jitkova Yulia Y Zhao Ran R St-Germain Jonathan J Heese Lauren E LE Egan Grace G Ruvolo Vivian R VR Barghout Samir H SH Nishida Yuki Y Hurren Rose R Ma Wencai W Gronda Marcela M Link Todd T Wong Keith K Mabanglo Mark M Kojima Kensuke K Borthakur Gautam G MacLean Neil N Ma Man Chun John MCJ Leber Andrew B AB Minden Mark D MD Houry Walid W Kantarjian Hagop H Stogniew Martin M Raught Brian B Pai Emil F EF Schimmer Aaron D AD Andreeff Michael M

Cancer cell 20190502 5

The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activat ...[more]

PMID: 31056398

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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

Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.

Publications

Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.

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