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Publication

Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.

Cancer cell | 2019

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.

Pubmed ID: 31056398 RIS Download

Research resources used in this publication

Total OXPHOS Rodent WB Antibody Cocktail (RRID:AB_2629281) (antibody)

Additional research tools detected in this publication

Antibodies used in this publication

Associated grants

Agency: NCI NIH HHS, United States
Id: P30 CA016672
Agency: NCI NIH HHS, United States
Id: P50 CA100632
Agency: FDA HHS, United States
Id: R01 FD006118
Agency: CIHR, Canada

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This is a list of tools and resources that we have found mentioned in this publication.

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