Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality

Cancer Cell. 2019 May 13;35(5):721-737.e9. doi: 10.1016/j.ccell.2019.03.014. Epub 2019 May 2.


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.

Keywords: acute myeloid leukemia; cancer; imipridone; lymphoma; mitochondrial ClpP; mitochondrial proteolysis; oxidative phosphorylation; respiratory chain complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Endopeptidase Clp / chemistry
  • Endopeptidase Clp / genetics*
  • Endopeptidase Clp / metabolism*
  • Female
  • HCT116 Cells
  • HEK293 Cells
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage*
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Imidazoles
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Mice
  • Mitochondria / metabolism*
  • Models, Molecular
  • Point Mutation
  • Protein Conformation / drug effects
  • Proteolysis
  • Pyridines
  • Pyrimidines
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays


  • Heterocyclic Compounds, 4 or More Rings
  • Imidazoles
  • Pyridines
  • Pyrimidines
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • TIC10 compound
  • ClpP protein, human
  • Endopeptidase Clp