Laboratory of Organic Chemistry, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
Org Biomol Chem. 2021 Mar 28;19(12):2681-2687. doi: 10.1039/d0ob02259d. Epub 2021 Feb 26.
Redox homeostasis is essential for cell function and its disruption is associated with multiple pathologies. Redox balance is largely regulated by the relative concentrations of reduced and oxidized glutathione. In eukaryotic cells, this ratio is different in each cell compartment, and disruption of the mitochondrial redox balance has been specifically linked to metabolic diseases. Here, we report a probe that is selectively activated by endogenous nitroreductases, and releases tributylphosphine to trigger redox stress in mitochondria. Mechanistic studies revealed that, counterintuitively, release of a reducing agent in mitochondria rapidly induced oxidative stress through accumulation of superoxide. This response is mediated by glutathione, suggesting a link between reductive and oxidative stress. Furthermore, mitochondrial redox stress activates a cellular response orchestrated by transcription factor ATF4, which upregulates genes involved in glutathione catabolism.
氧化还原平衡对细胞功能至关重要，其失衡与多种病理有关。氧化还原平衡在很大程度上受还原型和氧化型谷胱甘肽相对浓度的调节。在真核细胞中，每个细胞区室的比值都不同，线粒体氧化还原平衡的破坏与代谢疾病特别相关。在这里，我们报告了一种探针，它可被内源性硝基还原酶选择性激活，并释放三丁基膦以引发线粒体中的氧化应激。机制研究表明，出乎意料的是，线粒体中还原剂的释放会通过超氧化物的积累迅速诱导氧化应激。这种反应是由谷胱甘肽介导的，表明还原性应激和氧化性应激之间存在联系。此外，线粒体氧化还原应激激活由转录因子 ATF4 协调的细胞反应，上调参与谷胱甘肽分解代谢的基因。
