Tetrahydrobiopterin metabolism attenuates ROS generation and radiosensitivity through LDHA S-nitrosylation: novel insight into radiogenic lung injury

作者：Yang Feng, Yahui Feng, Liming Gu, Wei Mo, Xi Wang, Bin Song, Min Hee Hong, Fenghao Geng, Pei Huang, Hongying Yang, Wei Zhu, Yang Jiao, Qi Zhang, Wei‐Qun Ding, Jianping Cao, Shuyu Zhang · 发表于：Experimental & Molecular Medicine · 年份：2024 · DOI：10.1038/s12276-024-01208-z · 被引用次数：22 · 研究领域：Nitric Oxide and Endothelin Effects、Redox biology and oxidative stress、Electron Spin Resonance Studies

Abstract Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice ( Gch1 fl/fl ; Sftpa1-Cre +/− mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice ( Gch1 lsl/lsl ; Sftpa1-Cre +/− mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could r...