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\xa0by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation\xa0of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory\xa0chain 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\xa0suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.