TY - JOUR TI - Characterizing the role of mitochondria in the toxicity of trichothecenes produced by Fusarium graminearum DO - https://doi.org/doi:10.7282/T3QJ7FDJ PY - 2014 AB - Fusarium graminearum is a toxigenic fungal pathogen infecting economically significant cereal crops. Trichothecenes are a large family of low molecular weight sesquiterpenoid mycotoxins synthesized by F. graminearum and other fungi and are among the most toxic compounds known to man. These mycotoxins and their producers are encountered worldwide in the environment as natural contaminants of cereal grains presenting a high food safety risk for humans and cattle and threaten the global food supply. Trichothecene mycotoxicosis was primarily associated with their inhibitory effects on translation. However, these highly stable toxins also inhibit other cellular processes which contribute to their toxicity. In this work, using yeast as a model organism, a genome wide approach has been applied to obtain a comprehensive understanding of the molecular mechanism of the type A and B trichothecene toxicity. Due to their prevalence and impact, T-2 toxin and diacetoxyscirpenol (DAS) are used as representative type A toxins while trichothecin (Tcin) and deoxynivalenol (DON) are used as representative type B toxins. The yeast knockout collection of nonessential genes was initially used to identify mutant strains that exhibited increased resistance or susceptibility to trichothecenes. This screening led to identification of the role of mitochondria during trichothecene toxicity. The largest group of mutants exhibiting resistance was affected in their mitochondrial functions. Mitochondrial translation was directly inhibited, independent of total translation, and the trichothecene-treated cells exhibited severe fragmentation of mitochondrial membrane. Furthermore, actively respiring cells with functional mitochondria were essential for trichothecene cytotoxicity suggesting a critical role for mitochondria. A large fraction of the highly susceptible strains exhibited very high levels of reactive oxygen species (ROS) upon trichothecene treatment. Antioxidants increased cell survival and reduced mitochondrial membrane damage in trichothecene-treated cells. The direct role for ROS in mediating trichothecene cytotoxicity was confirmed when two novel Arabidopsis nonspecific lipid transfer proteins that mediated resistance to trichothecenes in A. thaliana exhibited antioxidant property and rescued trichothecene-treated yeast cells. Rapamycin-induced mitophagy reduced ROS levels and increased survival in trichothecene-treated cells suggesting mitophagy as a novel prosurvival cellular mechanism during oxidative stress in trichothecene-treated cells. KW - Microbiology and Molecular Genetics KW - Mitochondrial pathology KW - Fusarium KW - Yeast fungi--Biotechnology LA - eng ER -