title: From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect in Caenorhabditis elegans.
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.
authors.affiliation: *Nicholas School of the Environment, Duke University, Durham, North Carolina joel.meyer@duke.edu.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Luz
authors.affiliation: *Nicholas School of the Environment, Duke University, Durham, North Carolina.
authors.forename: Tewodros R
authors.initials: TR
authors.lastname: Godebo
authors.affiliation: Duke Molecular Physiology Institute.
authors.forename: Dhaval P
authors.initials: DP
authors.lastname: Bhatt
authors.affiliation: Duke Molecular Physiology Institute Sarah W. Stedman Nutrition and Metabolism Center.
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: *Nicholas School of the Environment, Duke University, Durham, North Carolina.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Maurer
authors.affiliation: Duke Molecular Physiology Institute Sarah W. Stedman Nutrition and Metabolism Center Departments of Medicine and Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hirschey
authors.affiliation: *Nicholas School of the Environment, Duke University, Durham, North Carolina joel.meyer@duke.edu.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Meyer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000378:metabolism; D056915:DNA Copy Number Variations; D004579:Electron Transport; D006019:Glycolysis; D013058:Mass Spectrometry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D055432:Metabolomics; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D010101:Oxygen Consumption / Q000187:drug effects*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D018053:Arsenites; D011768:Pyruvate Dehydrogenase Complex; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; C015001:arsenite
keywords: Caenorhabditis elegans; Warburg effect; arsenite; mitochondrial toxicity.