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To identify cellular functions that provide resistance to trichothecenes, we screened the yeast deletion library for increased sensitivity to trichothecin and identified a vital role for mitochondrial oxidative stress in trichothecene sensitivity and for mitophagy in protecting cells against trichothecenes. Our data show that enhancing degradation of trichothecene-damaged mitochondria by mitophagy reduces mitochondrial oxidative stress and increases cell survival. 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