Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae*

Lazard, Myriam; Dauplais, Marc; Blanquet, Sylvain; Plateau, Pierre

doi:10.1074/jbc.m115.640375

Cited by 45 publications

(34 citation statements)

References 60 publications

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“…The exact mechanisms through which Se-Met exerts its powerful toxicity are still not well understood, but they may include nonspecific incorporation into proteins by entering the methionine pool and thus inducing translational changes [22]. Furthermore, Se-Met may exert its toxicity by increasing the oxidative stress [23,24,25], and oxidative stress has long been recognized as a major toxic effect of selenium species, in intriguing coexistence with the antioxidant activity of selenium-containing enzymes, inducible by selenium itself and several other stressors [26]. Therefore, it is possible that our finding of an excess Se-Met content in the CSF of our ALS patients represents a relevant factor in disease etiology.…”

Section: Discussionmentioning

confidence: 99%

Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations

Mandrioli¹,

Michalke

Solovyev

et al. 2017

Neurodegener Dis

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Background: Although an increasing role of genetic susceptibility has been recognized, the role of environmental risk factors in amyotrophic lateral sclerosis (ALS) etiology is largely uncertain; among neurotoxic chemicals, epidemiological and biological plausibility has been provided for pesticides, the heavy metal lead, the metalloid selenium, and other persistent organic pollutants. Selenium involvement in ALS has been suggested on the basis of epidemiological studies, in vitro investigations, and veterinary studies in which selenium induced a selective toxicity against motor neurons. Objective: Hypothesizing a multistep pathogenic mechanism (genetic susceptibility and environmental exposure), we aimed to study selenium species in ALS patients carrying disease-associated gene mutations as compared to a series of hospital controls. Methods: Using advanced analytical techniques, we determined selenium species in cerebrospinal fluid sampled at diagnosis in 9 ALS patients carrying different gene mutations (C9ORF72, SOD1, FUS, TARDBP, ATXN2, and TUBA4A) compared to 42 controls. Results: In a patient with the tubulin-related TUBA4A mutation, we found highly elevated levels (in μg/L) of glutathione-peroxidase-bound selenium (32.8 vs. 1.0) as well as increased levels of selenoprotein-P-bound selenium (2.4 vs. 0.8), selenite (1.8 vs. 0.1), and selenate (0.9 vs. 0.1). In the remaining ALS patients, we detected elevated selenomethionine-bound selenium levels (0.38 vs. 0.06). Conclusions: Selenium compounds can impair tubulin synthesis and the cytoskeleton structure, as do tubulin-related gene mutations. The elevated selenium species levels in the TUBA4A patient may have a genetic etiology and/or represent a pathogenic pathway through which this mutation favors disease onset, though unmeasured confounding cannot be excluded. The elevated selenomethionine levels in the other patients are also of interest due to the toxicity of this nonphysiological selenium species. Our study is the first to assess selenium exposure in genetic ALS, suggesting an interaction between this environmental factor and genetics in triggering disease onset.

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Section: Discussionmentioning

confidence: 99%

Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations

Mandrioli¹,

Michalke

Solovyev

et al. 2017

Neurodegener Dis

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“…Such a disparity may be partly explained by the strong inverse dependency of SeMet toxicity on the methionine concentration in the growth medium of yeast or mammalian cell cultures (113,131). This dependency indicates that SeMet and methionine share common uptake and/or metabolic pathways.…”

Section: Selenomethionine Toxicitymentioning

confidence: 99%

“…Suzuki et al (138) reported that SeMet induced ROS generation and apoptosis in lung cancer A549 cells (138). Superoxide production was observed in SeMet-treated yeast cells and deletion of SOD1, the gene coding for superoxide dismutase, was shown to increase SeMet toxicity (113). In addition, metabolomic studies in yeast demonstrated that SeMet addition induced a redox imbalance (149,150).…”

Section: Selenomethionine Toxicitymentioning

confidence: 99%

“…To gain insights into the metabolic product(s) underlying SeMet toxicity, we compared the sensitivity to SeMet of several S. cerevisiae mutants compromised in individual pathways of sulfur metabolism (113). This analysis allowed us to exclude effects resulting from an accumulation of SeAM, SeAH or any compound in the methionine salvage pathway.…”

Section: Selenomethionine Toxicitymentioning

confidence: 99%

“…Oxidation of SeCys to the diselenide form is fast at neutral pH [<10 min vs. >10 h for cysteine, in identical conditions (113)]. For this reason, most toxicity studies were performed starting from SeCystine, which is easily reduced intracellularly into SeCys, either by GSH (114), or by the Trx and Grx systems (69).…”

Section: Selenocyst(e)ine Toxicitymentioning

confidence: 99%

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Recent advances in the mechanism of selenoamino acids toxicity in eukaryotic cells

Lazard

Dauplais

Blanquet

et al. 2017

Biomolecular Concepts

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Selenium is an essential trace element due to its incorporation into selenoproteins with important biological functions. However, at high doses it is toxic. Selenium toxicity is generally attributed to the induction of oxidative stress. However, it has become apparent that the mode of action of seleno-compounds varies, depending on its chemical form and speciation. Recent studies in various eukaryotic systems, in particular the model organism Saccharomyces cerevisiae, provide new insights on the cytotoxic mechanisms of selenomethionine and selenocysteine. This review first summarizes current knowledge on reactive oxygen species (ROS)-induced genotoxicity of inorganic selenium species. Then, we discuss recent advances on our understanding of the molecular mechanisms of selenocysteine and selenomethionine cytotoxicity. We present evidences indicating that both oxidative stress and ROSindependent mechanisms contribute to selenoamino acids cytotoxicity. These latter mechanisms include disruption of protein homeostasis by selenocysteine misincorporation in proteins and/or reaction of selenols with protein thiols.

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Biomimetic Metal–Organic Framework Combats Biofilm‐Associated Infections via Hyperthermia‐Enhanced Bacterial Metabolic Interference and Autophagy‐Promoted Adaptive Immunity

Hu,

Ma,

Zhang

et al. 2023

Adv Funct Materials

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Robust bacterial metabolism and the immunosuppression on peripheral immune cells cause biofilm‐associated infections (BAIs) extremely refractory to be eradicated via antibiotics alone. Herein, hierarchical mesoporous UiO‐66 metal–organic framework is decorated with selenite, polypyrrole, and macrophage membrane (MM) to develop a biomimetic nanosphere (USPM). Following the recruitment of USPM to the biofilm microenvironment (BME) via the pathogen‐targeting ability derived from MM. The BME‐responsive USPM can precisely release selenite to penetrate the loosened biofilm in synergy with near‐infrared‐induced mild photothermal therapy (mPTT). Selenite can quickly react with reducing substances to generate hydrogen selenide (H2Se) inside the biofilm. H2Se can competitively inhibit bacterial metabolic processes and disrupt biofilm metabolic homeostasis by cascade amplification effects. Furthermore, H2Se inside the biofilm further sensitizes photothermia to exert a precise local photothermal effect. Outside the biofilm, USPM can simultaneously promote the phagocytosis and autophagy of macrophages to kill and decompose the phagocytosed bacteria. Finally, the well‐decomposed bacterial antigens in macrophages can be presented to antigen‐presenting cells to arouse adaptive immune responses and enhance anti‐biofilm effectiveness further. Such powerful mPTT‐enhanced bacterial metabolic disruption and macrophagic autophagy‐promoted adaptive immune activation suggest an alternative therapeutic strategy to cure refractory BAIs.

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Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae*

Cited by 45 publications

References 60 publications

Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations

Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations

Recent advances in the mechanism of selenoamino acids toxicity in eukaryotic cells

Biomimetic Metal–Organic Framework Combats Biofilm‐Associated Infections via Hyperthermia‐Enhanced Bacterial Metabolic Interference and Autophagy‐Promoted Adaptive Immunity

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