title: Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes.
abstract: Trichothecene mycotoxins are natural contaminants of small grain cereals and are encountered in the environment, posing a worldwide threat to human and animal health. Their mechanism of toxicity is poorly understood, and little is known about cellular protection mechanisms against trichothecenes. We previously identified inhibition of mitochondrial protein synthesis as a novel mechanism for trichothecene-induced cell death. To identify cellular functions involved in trichothecene resistance, we screened the Saccharomyces cerevisiae deletion library for increased sensitivity to nonlethal concentrations of trichothecin (Tcin) and identified 121 strains exhibiting higher sensitivity than the parental strain. The largest group of sensitive strains had significantly higher reactive oxygen species (ROS) levels relative to the parental strain. A dose-dependent increase in ROS levels was observed in the parental strain treated with different trichothecenes, but not in a petite version of the parental 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 oxidative stress contributes to trichothecene sensitivity. Cotreatment with rapamycin and trichothecenes reduced ROS levels and cytotoxicity in the parental strain relative to the trichothecene treatment alone, but not in mitophagy deficient mutants, suggesting that elimination of trichothecene-damaged mitochondria by mitophagy improves cell survival. These results reveal that increased mitophagy is a cellular protection mechanism against trichothecene-induced mitochondrial oxidative stress and a potential target for trichothecene resistance.
authors: Department of Plant Biology and Pathology, School of Environmental and Biological Sciences, Rutgers, the State University of New Jersey, New Brunswick, NJ 08901; and.
authors: Mohamed Anwar
authors: MA
authors: Bin-Umer
authors: Department of Plant Biology and Pathology, School of Environmental and Biological Sciences, Rutgers, the State University of New Jersey, New Brunswick, NJ 08901; and.
authors: John E
authors: JE
authors: McLaughlin
authors: Department of Plant Biology and Pathology, School of Environmental and Biological Sciences, Rutgers, the State University of New Jersey, New Brunswick, NJ 08901; and.
authors: Matthew S
authors: MS
authors: Butterly
authors: Bacterial Foodborne Pathogens and Mycology Unit, National Center for Agricultural Utilization Research, Agricultural Research Service, US Department of Agriculture, Peoria, IL 61604.
authors: Susan
authors: S
authors: McCormick
authors: Department of Plant Biology and Pathology, School of Environmental and Biological Sciences, Rutgers, the State University of New Jersey, New Brunswick, NJ 08901; and tumer@aesop.rutgers.edu.
authors: Nilgun E
authors: NE
authors: Tumer
mesh_terms: D000818:Animals; D025141:Drug Resistance, Fungal / Q000235:genetics; D005506:Food Contamination; D059022:Food Safety; D055786:Gene Knockout Techniques; D005800:Genes, Fungal; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D014255:Trichothecenes / Q000633:toxicity*
chemical_list: D017382:Reactive Oxygen Species; D014255:Trichothecenes; D020123:Sirolimus
keywords: Fusarium graminearum; Fusarium head blight; deoxynivalenol