期刊
TOXICOLOGICAL SCIENCES
卷 152, 期 2, 页码 349-362出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfw093
关键词
arsenite; Warburg effect; Caenorhabditis elegans; mitochondrial toxicity
类别
资金
- Duke Cancer Institute as part of the P30 Cancer Center Support Grant [P30 CA014236]
- National Institute of Environmental Health Sciences
- National Institute of Health [R01-ES017540-01A2, P42ES010356]
- National Institute of Health, Office of Research Infrastructure Programs [P40 OD010440]
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.
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