Dioctatin Activates ClpP to Degrade Mitochondrial Components and Inhibits Aflatoxin Production

Cell Chem Biol. 2020 Nov 19;27(11):1396-1409.e10. doi: 10.1016/j.chembiol.2020.08.006. Epub 2020 Sep 3.


Aflatoxin contamination of crops is a serious problem worldwide. Utilization of aflatoxin production inhibitors is attractive, as the elucidation of their modes of action contributes to clarifying the mechanism of aflatoxin production. Here, we identified mitochondrial protease ClpP as the target of dioctatin, an inhibitor of aflatoxin production of Aspergillus flavus. Dioctatin conferred uncontrolled caseinolytic capacity on ClpP of A. flavus and Escherichia coli. Dioctatin-bound ClpP selectively degraded mitochondrial energy-related proteins in vitro, including a subunit of respiratory chain complex V, which was also reduced by dioctatin in a ClpP-dependent manner in vivo. Dioctatin enhanced glycolysis and alcohol fermentation while reducing tricarboxylic acid cycle metabolites. These disturbances were accompanied by reduced histone acetylation and reduced expression of aflatoxin biosynthetic genes. Our results suggest that dioctatin inhibits aflatoxin production by inducing ClpP-mediated degradation of mitochondrial energy-related components, and that mitochondrial energy metabolism functions as a key determinant of aflatoxin production.

Keywords: 2D-DIGE; Aspergillus flavus; Clp protease; aflatoxin; dioctatin; metabolomic analysis; target identification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aflatoxins / antagonists & inhibitors*
  • Aflatoxins / biosynthesis
  • Aflatoxins / genetics
  • Aspergillus flavus / enzymology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Citric Acid Cycle / drug effects*
  • Dose-Response Relationship, Drug
  • Energy Metabolism / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / enzymology
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Molecular Structure
  • Serine Endopeptidases / metabolism


  • Aflatoxins
  • Bacterial Proteins
  • Enzyme Inhibitors
  • ClpP2 protein, bacteria
  • Serine Endopeptidases