Ceramide-1-phosphate alleviates high-altitude pulmonary edema by stabilizing circadian ARNTL-mediated mitochondrial dynamics

作者：Liuyang Tian, Chenghui Zhao, Yan Yan, Qian Jia, Saijia Cui, Huining Chen, Xiaolu Li, Hongfeng Jiang, Yong-ming Yao, Kunlun He, Xiaojing Zhao · 发表于：Journal of Advanced Research · 年份：2023 · DOI：10.1016/j.jare.2023.07.008 · 被引用次数：23 · 研究领域：Sphingolipid Metabolism and Signaling、High Altitude and Hypoxia、Inflammasome and immune disorders

INTRODUCTION: High-altitude pulmonary edema (HAPE) is a severe and potentially fatal condition with limited treatment options. Although ceramide kinase (CERK)-derived ceramide-1-phosphate (C1P) has been demonstrated to offer protection against various pulmonary diseases, its effects on HAPE remain unclear. OBJECTIVES: Our study aimed to investigate the potential role of CERK-derived C1P in the development of HAPE and to reveal the molecular mechanisms underlying its protective effects. We hypothesized that CERK-derived C1P could protect against HAPE by stabilizing circadian rhythms and maintaining mitochondrial dynamics. METHODS: To test our hypothesis, we used CERK-knockout mice and established HAPE mouse models using a FLYDWC50-1C hypobaric hypoxic cabin. We utilized a range of methods, including lipidomics, transcriptomics, immunofluorescence, Western blotting, and transmission electron microscopy, to identify the mechanisms of regulation. RESULTS: Our findings demonstrated that CERK-derived C1P played a protective role against HAPE. Inhibition of CERK exacerbated HAPE induced by the hypobaric hypoxic environment. Specifically, we identified a novel mechanism in which CERK inhibition induced aryl hydrocarbon receptor nuclear translocator-like (ARNTL) autophagic degradation, inducing the circadian rhythm and triggering mitochondrial damage by controlling the expression of proteins required for mitochondrial fission and fusion. The decreased ARNTL caused by CERK inhibition i...