RRC ID 53526
著者 Luz AL, Godebo TR, Bhatt DP, Ilkayeva OR, Maurer LL, Hirschey MD, Meyer JN.
タイトル From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect in Caenorhabditis elegans.
ジャーナル Toxicol Sci
Abstract Millions of people worldwide are chronically exposed to arsenic through contaminated drinking water. Despite decades of research studying the carcinogenic potential of arsenic, the mechanisms by which arsenic causes cancer and other diseases remain poorly understood. Mitochondria appear to be an important target of arsenic toxicity. The trivalent arsenical, arsenite, can induce mitochondrial reactive oxygen species production, inhibit enzymes involved in energy metabolism, and induce aerobic glycolysis in vitro, suggesting that metabolic dysfunction may be important in arsenic-induced disease. Here, using the model organism Caenorhabditis elegans and a novel metabolic inhibition assay, we report an in vivo induction of aerobic glycolysis following arsenite exposure. Furthermore, arsenite exposure induced severe mitochondrial dysfunction, including altered pyruvate metabolism; reduced steady-state ATP levels, ATP-linked respiration and spare respiratory capacity; and increased proton leak. We also found evidence that induction of autophagy is an important protective response to arsenite exposure. Because these results demonstrate that mitochondria are an important in vivo target of arsenite toxicity, we hypothesized that deficiencies in mitochondrial electron transport chain genes, which cause mitochondrial disease in humans, would sensitize nematodes to arsenite. In agreement with this, nematodes deficient in electron transport chain complexes I, II, and III, but not ATP synthase, were sensitive to arsenite exposure, thus identifying a novel class of gene-environment interactions that warrant further investigation in the human populace.
巻・号 152(2)
ページ 349-62
公開日 2016-8-1
DOI 10.1093/toxsci/kfw093
PII kfw093
PMID 27208080
PMC PMC4960910
MeSH Adenosine Triphosphate / metabolism Animals Arsenites / toxicity* Caenorhabditis elegans / drug effects* Caenorhabditis elegans / metabolism DNA Copy Number Variations Electron Transport Glycolysis Mass Spectrometry Membrane Potential, Mitochondrial / drug effects Metabolomics Mitochondria / drug effects* Mitochondria / metabolism Mutation Oxygen Consumption / drug effects* Pyruvate Dehydrogenase Complex / metabolism Pyruvic Acid / metabolism
IF 3.564
引用数 14
リソース情報
線虫 tm760 tm776 tm1146