Natural variation in C. Elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism

Stefan Zdraljevic, Bennett William Fox, Christine Strand, Oishika Panda, Francisco J. Tenjo, Shannon C. Brady, Tim A. Crombie, John G. Doench, Frank C. Schroeder, Erik Christian Andersen*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology. Editorial note:This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Original languageEnglish (US)
Article numbere40260
JournaleLife
Volume8
DOIs
StatePublished - Apr 1 2019

Fingerprint

Branched Chain Amino Acids
Arsenic
Metabolism
Toxicity
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Caenorhabditis elegans
Fatty Acids
Genes
Peer Review
Metabolomics
Physiology
Cells
Population

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Zdraljevic, Stefan ; Fox, Bennett William ; Strand, Christine ; Panda, Oishika ; Tenjo, Francisco J. ; Brady, Shannon C. ; Crombie, Tim A. ; Doench, John G. ; Schroeder, Frank C. ; Andersen, Erik Christian. / Natural variation in C. Elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism. In: eLife. 2019 ; Vol. 8.
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abstract = "We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology. Editorial note:This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).",
author = "Stefan Zdraljevic and Fox, {Bennett William} and Christine Strand and Oishika Panda and Tenjo, {Francisco J.} and Brady, {Shannon C.} and Crombie, {Tim A.} and Doench, {John G.} and Schroeder, {Frank C.} and Andersen, {Erik Christian}",
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Zdraljevic, S, Fox, BW, Strand, C, Panda, O, Tenjo, FJ, Brady, SC, Crombie, TA, Doench, JG, Schroeder, FC & Andersen, EC 2019, 'Natural variation in C. Elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism', eLife, vol. 8, e40260. https://doi.org/10.7554/eLife.40260

Natural variation in C. Elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism. / Zdraljevic, Stefan; Fox, Bennett William; Strand, Christine; Panda, Oishika; Tenjo, Francisco J.; Brady, Shannon C.; Crombie, Tim A.; Doench, John G.; Schroeder, Frank C.; Andersen, Erik Christian.

In: eLife, Vol. 8, e40260, 01.04.2019.

Research output: Contribution to journalArticle

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AU - Zdraljevic, Stefan

AU - Fox, Bennett William

AU - Strand, Christine

AU - Panda, Oishika

AU - Tenjo, Francisco J.

AU - Brady, Shannon C.

AU - Crombie, Tim A.

AU - Doench, John G.

AU - Schroeder, Frank C.

AU - Andersen, Erik Christian

PY - 2019/4/1

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N2 - We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology. Editorial note:This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

AB - We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology. Editorial note:This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

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