Department of Chemistry & Biochemistry, Laurentian University, Sudbury, ON, Canada P3E 2C6.
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Free Radic Biol Med. 2017 Dec;113:323-334. doi: 10.1016/j.freeradbiomed.2017.10.011. Epub 2017 Oct 12.
Oxidative stress results in substantial biochemical and physiological perturbations in essentially all organisms. To determine the broad metabolic effects of oxidative stress, we have quantified the response in Drosophila melanogaster to both genetically and environmentally derived oxidative stress. Flies were challenged with loss of Superoxide dismutase activity or chronic or acute exposure to the oxidizing chemical paraquat. Metabolic changes were then quantified using a recently developed chemical isotope labeling (CIL) liquid chromatography - mass spectrometry (LC-MS) platform that targets the carboxylic acid and amine/phenol submetabolomes with high metabolic coverage. We discovered wide spread changes in both submetabolomes in response to all three types of stresses including: changes to the urea cycle, tryptophan metabolism, porphyrin metabolism, as well as a series of metabolic pathways involved in glutathione synthesis. Strikingly, while there are commonalities across the conditions, all three resulted in different metabolomic responses, with the greatest difference between the genetic and environmental responses. Genetic oxidative stress resulted in substantially more widespread effects, both in terms of the percent of the metabolome altered, and the magnitude of changes in individual metabolites. Chronic and acute environmental stress resulted in more similar responses although both were distinct from genetic stress. Overall, these results indicate that the metabolomic response to oxidative stress is complex, reaching across multiple metabolic pathways, with some shared features but with more features unique to different, specific stressors.
氧化应激会导致几乎所有生物体的大量生化和生理紊乱。为了确定氧化应激的广泛代谢效应，我们已经量化了果蝇对遗传和环境引起的氧化应激的反应。通过使用最近开发的化学同位素标记（CIL）液相色谱-质谱（LC-MS）平台，我们对果蝇进行了超氧化物歧化酶活性丧失或慢性或急性暴露于氧化化学物质百草枯的挑战，该平台针对羧酸和胺/酚亚代谢组进行了高代谢覆盖。我们发现，三种类型的应激都广泛地改变了两个亚代谢组，包括：尿素循环、色氨酸代谢、卟啉代谢的改变，以及一系列参与谷胱甘肽合成的代谢途径。引人注目的是，尽管所有条件都有共同之处，但所有三种条件都导致了不同的代谢组学反应，遗传和环境反应之间的差异最大。遗传氧化应激导致更广泛的影响，无论是在代谢组改变的百分比方面，还是在单个代谢物变化的幅度方面。慢性和急性环境应激导致更相似的反应，尽管两者都与遗传应激不同。总的来说，这些结果表明，氧化应激的代谢组学反应是复杂的，涉及多个代谢途径，具有一些共同的特征，但也有更多特定于不同特定应激源的特征。
