Title: Elimination of damaged mitochondria through mitophagy reduces trichothecene mycotoxin mediated mitochondrial oxidative stress and enhances survival of Saccharomyces cerevisiae Authors
|Bin-Umer, Mohamed -|
|Mclaughlin, John -|
|Butterly, Matthew -|
|Tumer, Nilgun -|
Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 27, 2014
Publication Date: N/A
Interpretive Summary: Fusarium Head Blight (FHB), a disease of cereal crops, is caused by a fungus that produces trichothecene mycotoxins. Trichothecene contamination of grain has serious economic and health impacts, and the toxins are important factors in determining the severity of the disease. One strategy to combat FHB and improve food safety is to modify genes in cereals to make plants less sensitive to the toxins. In this research, we screened a collection of yeast mutants with specific gene deletions for those with sensitivity or tolerance to trichothecenes. Treatment with antioxidants alleviated oxidative stress in the sensitive yeast exposed to trichothecenes. This research showed that elimination of trichothecene-damaged mitochondria reduces toxin sensitivity in yeast and may provide a novel approach to reduce FHB severity and toxin contamination of grain.
Technical Abstract: Trichothecene mycotoxins are natural contaminants of small grain cereals. Trichothecenes block protein synthesis and chronic exposure to these toxins can cause inhibition of multiple cellular processes, including cytostolic and mitochondrial translation. To identify cellular functions involved in trichothecene resistance, we screened the Saccharomyces cerevisiae deletion library for increased sensitivity to nonlethal concentrations of trichothecin and identified 121 strains exhibiting higher sensitivity than the parental strain. The largest group of sensitive strains was affected in oxidative stress and autophagic processes, including mitophagy. Reactive oxygen species (ROS) levels were higher in the most sensitive strains relative to the parental strain. A dose-dependent increase in ROS levels was observed in parental strain treated with different trichothecenes, but not in a petite strain or in the presence of a mitochondrial membrane uncoupler, indicating that mitochondria are the main site of ROS production due to toxin exposure. Cytotoxicity of trichothecenes was alleviated after treatment of the parental strain and highly sensitive mutants with antioxidants, suggesting that toxicity of trichothecenes is a direct consequence of oxidative stress. Co-treatment with rapamycin and trichothecenes reduced ROS levels and cytotoxicity in the parental strain relative to the trichothecene treatment alone, but not in the mitophagy deficient mutants, suggesting that elimination of ROS-producing mitochondria by mitophagy improves cell survival. These results demonstrate that increased mitophagy is a cellular protection mechanism against trichothecene-induced mitochondrial oxidative stress and suggest that elimination of damaged mitochondria through mitophagy may confer resistance to trichothecenes.