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

Author:

Zdraljevic Stefan12ORCID,Fox Bennett William3,Strand Christine4,Panda Oishika35,Tenjo Francisco J3,Brady Shannon C12,Crombie Tim A2,Doench John G4ORCID,Schroeder Frank C3,Andersen Erik C126ORCID

Affiliation:

1. Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, United States

2. Department of Molecular Biosciences, Northwestern University, Evanston, United States

3. Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States

4. Broad Institute of MIT and Harvard, Cambridge, United States

5. The Buck Institute for Research on Aging, Novato, United States

6. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, United States

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 (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

Funder

National Institute of General Medical Sciences

National Institute of Diabetes and Digestive and Kidney Diseases

American Cancer Society

National Institute of Environmental Health Sciences

Next Generation Fund

Sherman-Fairchild Cancer Innovation Award

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Cited by 66 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3