Dioctatin Unregulates ClpP to Degrade Mitochondrial Components and Inhibits Aflatoxin Production

Aflatoxin contamination of crops is a serious problem impacting human health and the economy. Utilization of aflatoxin production inhibitors is attractive, as the elucidation of their modes of action provides clues to clarify the mechanism of aflatoxin production. Here, we identified mitochondrial protease ClpP as the molecular target of dioctatin, an inhibitor of aflatoxin production of Aspergillus flavus. Dioctatin conferred uncontrolled caseinolytic capacity on ClpP of A. flavus and Escherichia coli. Proteomic analysis showed that dioctatin-bound ClpP selectively degraded mitochondrial energy-related proteins, such as subunits of respiratory complexes and the pyruvate dehydrogenase complex. Dioctatin enhanced glycolysis and alcohol fermentation while reducing tricarboxylic acid cycle metabolites. These metabolic shifts accompanied the reduction of histone acetylation, leading to the downregulation of aflatoxin production. Our results suggest the existence of an exquisite balance between aflatoxin production and alcohol fermentation, with mitochondrial status serving as a key determinant of this balance.