Trichothecene Mycotoxins Inhibit Mitochondrial Translation—Implication for the Mechanism of Toxicity

Bin-Umer, Mohamed Anwar; McLaughlin, J.; Basu, Debaleena; McCormick, Susan P.; Tumer, Nilgun E.

doi:10.3390/toxins3121484

Cited by 59 publications

(39 citation statements)

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“…These results reveal a previously unidentified mechanism against trichothecenes. media (0.75 μM) (12,13). Analysis of the identified strains revealed a vital role for mitochondrial oxidative stress in trichothecene sensitivity and provided the first evidence to our knowledge for a prosurvival role for the autophagic degradation of damaged mitochondria or mitophagy in the reduction of trichothecene-mediated mitochondrial oxidative stress.…”

Section: Significancementioning

confidence: 87%

“…2B) dropped at 6 h, possibly due to depolarization of the mitochondrial membrane (13). The decrease in mitochondrial membrane potential (13) may ultimately lead to further damage to mitochondria and other cellular functions and to eventual cell death.…”

Section: Discussionmentioning

confidence: 98%

“…To identify cellular genes that increase resistance to trichothecenes, we systematically screened the 4,720 nonessential S. cerevisiae deletion strains for increased sensitivity to 1 μM Tcin, which is nonlethal to the parental strain, BY4743 (12,13). The screen was repeated four times, and 121 strains consistently exhibiting higher sensitivity than the parental strain were identified (Table S1).…”

Section: Genome-wide Profiling Of Yeast Knockout Mutants Reveals a Romentioning

confidence: 99%

“…To understand the trichothecene mechanism of action, we previously carried out a genome-wide screen of Saccharomyces cerevisiae for resistance to trichothecin (Tcin) and showed that the largest group of resistant strains were affected in mitochondrial functions (12). We showed that trichothecenes inhibit mitochondrial translation, before depolarization and fragmentation of the mitochondrial membrane and independent of the cytosolic translation inhibition (12,13). Previous studies showed a link between ROS generation and mitochondrial translation (14,15).…”

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confidence: 99%

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Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes

Bin-Umer

McLaughlin

Butterly

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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.Fusarium head blight | deoxynivalenol | Fusarium graminearum

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Section: Significancementioning

confidence: 87%

Section: Discussionmentioning

confidence: 98%

Section: Genome-wide Profiling Of Yeast Knockout Mutants Reveals a Romentioning

confidence: 99%

mentioning

confidence: 99%

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Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes

Bin-Umer

McLaughlin

Butterly

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…These effects are mediated by interaction of DON with the ribosome and phosphorylation of ribosome associated mitogen-associated protein kinases (MAPK), which trigger immune responses including programmed cell death (Bae et al, 2010;Bae and Pestka, 2008;Zhou, 2003). However, the afore mentioned inhibition of cytosolic translation may not be the main cause of DON toxicity as recent studies in yeast showed that DON directly inhibits mitochondrial translation and that yeast cells lacking normal functioning mitochondria were resistant to otherwise lethal doses of DON (Bin-Umer et al, 2011McLaughlin et al, 2009). …”

Section: Don Inhibits Cytosolic As Well As Mitochondrial Protein Biosmentioning

confidence: 99%

Regulation and cell biology of secondary metabolite production in Fusarium graminearum and Fusarium pseudograminearum

Blum¹

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1 AbstractAscomycete fungi have the potential to produce a vast array of secondary metabolites, which are metabolites not required for normal growth and development. In any one species there is typically the potential for production of upward of fifty of these compounds. Many fungal secondary metabolites are used as medicines (e.g. penicillin or cyclosporine), or are of importance due to their toxicity in humans or animals (e.g. aflatoxins), or because they are virulence factors during crop plant infection (e.g. deoxynivalenol). Despite the vast potential encoded in ascomycete genomes, the vast majority of fungal secondary metabolites are yet to be discovered. This is in part due to our lack of understanding of how the production of these compounds is regulated. Moreover, even for the compounds we do know, we are just beginning to understand the complex interaction of external stimuli, signalling pathways, cellular and developmental biology that leads to their production. In this thesis, biological insights into these aspects of two fungal secondary metabolites, deoxynivalenol (DON) and fusatin are provided.In chapter II a high-throughput fluorescence activated cell sorting (FACS) based mutant screen was developed and the regulation of DON production in Fusarium graminearum was analysed. DON is an economically very important mycotoxin, as it is the most common contaminant of wheat, barley and corn worldwide. It is produced by plant pathogenic filamentous fungi of the Fusarium family, which can cause Fusarium head blight as well as Fusarium crown rot. During plant infection, DON is an important virulence factor and it can be toxic for humans and animals. The regulation of DON production is not yet fully understood. To identify regulators, a mutant screen was developed using FACS to allow high throughput screening, coupled with whole genome sequencing to identify mutations.Segregation analyses were performed to determine the mutation causing the phenotype.The mutant screen identified an adenylyl cyclase allele, which resulted in production of DON under normally repressive conditions. In addition, the mutant developed cellular structures associated with toxin production under repressive conditions. The levels of the fundamental second messenger cAMP, which adenylyl cyclases produce, were increased in the identified mutant, suggesting it might be a gain-of-function adenylyl cyclase mutant. This mutant screening methodology can be adapted to identify regulators of different secondary metabolites as well as to identify mutants overproducing yet unknown secondary metabolites. Abstract 2In chapter III the cell biology of DON production in Fusarium graminearum was elucidated with quantitative super resolution microscopy. During the last five years the first insights into the cell biology of DON production were gained, indicating complex cell biological mechanisms. During toxin production, F. graminearum develops endoplasmic reticulum proliferations, called toxisomes, at which two DON biosynthesis enzymes, TRI1 a...

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ADMEof Natural Toxins

González‐Pérez

Kroll

2012

Encyclopedia of Drug Metabolism and Interactions

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A common myth among the general public is that any substance derived from nature is inherently safe. To the contrary, some of the most potent and specifically‐targeted toxins have been identified and isolated from plants, mushrooms, and microorganisms. With regard to this volume, many of these toxins are of particular relevance in the pharmacokinetic study of xenobiotics, particularly their metabolism. This chapter highlights a select group of primarily small molecule toxins or protoxins of historical (i.e., aflatoxins) or contemporary (i.e., mycotoxins from “toxic mold”) relevance. Marine peptide toxins are intentionally omitted to maintain focus but are an additional class of highly‐selective acute and potentially lethal toxins from nature.

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Trichothecene Mycotoxins Inhibit Mitochondrial Translation—Implication for the Mechanism of Toxicity

Cited by 59 publications

References 45 publications

Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes

Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes

Regulation and cell biology of secondary metabolite production in Fusarium graminearum and Fusarium pseudograminearum

ADMEof Natural Toxins

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