Title: A Genome-Wide Screen in Saccharomyces cerevisiae Reveals a Critical Role for the Mitochondria in the Toxicity of a Trichothecene Mycotoxin Authors
|Mclaughlin, John -|
|Bin-Umer, Mohamed -|
|Tortora, Andrew -|
|Mendez, Natasha -|
|Turner, Nilgun -|
Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 22, 2009
Publication Date: December 9, 2009
Repository URL: http://doi: 10.1073/pnas.0909777106
Citation: Mclaughlin, J.E., Bin-Umer, M.A., Tortora, A., Mendez, N., Mccormick, S.P., Turner, N.E. 2009. A Genome-Wide Screen in Saccharomyces cerevisiae Reveals a Critical Role for the Mitochondria in the Toxicity of a Trichothecene Mycotoxin. Proceedings of the National Academy of Sciences. 106(51):21883-21888. doi: 10.107/pnas.0909777106. Interpretive Summary: In this research, we looked at a yeast deletion library to identify strains that are resistant to the ill-effects of trichothecene mycotoxins. Fusarium Head Blight, a disease of cereal crops, is caused by a fungus that produces these mycotoxins. The disease has serious economic and health impacts, and these toxins are important factors in determining the severity of the disease. One strategy to combat this disease is to modify genes in cereals, such as wheat and barley, to make the plants less sensitive to the toxins. We identified several genes that were previously unknown to play a role in trichothecene toxicity and demonstrated for the first time that mitochondrial membranes are critical for sensitivity to trichothecenes. Similar plant genes may provide novel targets for introducing resistance to trichothecene mycotoxins and Fusarium head blight in cereals.
Technical Abstract: Trichothecene mycotoxins synthesized by Fusarium species are potent inhibitors of eukaryotic translation. They are encountered in the environment and in food posing a threat to human and animal health. They have diverse roles in the cell that are not limited to the inhibition of protein synthesis. To develop a better understanding of the trichothecene mechanism of action, we screened the yeast knockout library to identify genes whose deletion confers resistance to trichothecin (Tcin). The largest group of resistant strains affected mitochondrial function, suggesting a role for fully active mitochondria in trichothecene toxicity. In vivo assays demonstrated that Tcin inhibits mitochondrial translation in the wild type strain, implicating mitochondrial translation as a previously unrecognized site of action. Mitochondrial translation was inhibited less by Tcin in the most resistant strains. The Tcin-resistant strains were cross-resistant to anisomycin and chloramphenicol, suggesting that Tcin targets the peptidyltransferase center of mitochondrial ribosomes. Tcin-induced cell death was partially rescued by mutants that regulate mitochondrial fusion and maintain the tubular morphology of mitochondria. Treatment of yeast cells with Tcin led to the fragmentation of the tubular mitochondrial network, supporting a role for Tcin in disruption of mitochondrial membrane morphology. These results provide genome-wide insight into the mode of action of trichothecene mycotoxins and uncover a critical role for the mitochondria in trichothecene toxicity.