Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism
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 causa...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/40260 |
| _version_ | 1811199504017260544 |
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| author | 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 C Andersen |
| author_facet | 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 C Andersen |
| author_sort | Stefan Zdraljevic |
| collection | DOAJ |
| description | 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). |
| first_indexed | 2024-04-12T01:49:11Z |
| format | Article |
| id | doaj.art-399d48554fb541b99853ddb37c526e13 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:49:11Z |
| publishDate | 2019-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-399d48554fb541b99853ddb37c526e132022-12-22T03:52:58ZengeLife Sciences Publications LtdeLife2050-084X2019-04-01810.7554/eLife.40260Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolismStefan Zdraljevic0https://orcid.org/0000-0003-2883-4616Bennett William Fox1Christine Strand2Oishika Panda3Francisco J Tenjo4Shannon C Brady5Tim A Crombie6John G Doench7https://orcid.org/0000-0002-3707-9889Frank C Schroeder8Erik C Andersen9https://orcid.org/0000-0003-0229-9651Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, United States; Department of Molecular Biosciences, Northwestern University, Evanston, United StatesBoyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United StatesBroad Institute of MIT and Harvard, Cambridge, United StatesBoyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States; The Buck Institute for Research on Aging, Novato, United StatesBoyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United StatesInterdisciplinary Biological Sciences Program, Northwestern University, Evanston, United States; Department of Molecular Biosciences, Northwestern University, Evanston, United StatesDepartment of Molecular Biosciences, Northwestern University, Evanston, United StatesBroad Institute of MIT and Harvard, Cambridge, United StatesBoyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United StatesInterdisciplinary Biological Sciences Program, Northwestern University, Evanston, United States; Department of Molecular Biosciences, Northwestern University, Evanston, United States; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, United StatesWe 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).https://elifesciences.org/articles/40260human cell linesenvironmental toxinnatural variation |
| spellingShingle | 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 C Andersen Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism eLife human cell lines environmental toxin natural variation |
| title | Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism |
| title_full | Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism |
| title_fullStr | Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism |
| title_full_unstemmed | Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism |
| title_short | Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism |
| title_sort | natural variation in c elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism |
| topic | human cell lines environmental toxin natural variation |
| url | https://elifesciences.org/articles/40260 |
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