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

This study provides evidence for the protective effect of C1P against HAPE, specifically, through stabilizing circadian rhythms and maintaining mitochondrial dynamics. Exogenous C1P therapy may be a promising strategy for treating HAPE. Our findings also highlight the importance of the circadian rhythm and mitochondrial dynamics in the pathogenesis of HAPE, suggesting that targeting these pathways may be a potential therapeutic approach for this condition.

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.

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 impaired mitochondrial dynamics, induced oxidative stress damage, and resulted in defects in mitophagy, particularly under hypoxia. Exogenous C1P prevented ARNTL degradation, alleviated mitochondrial damage, neutralized oxidative stress induced by CERK inhibition, and ultimately relieved HAPE. Conclusions: This study provides evidence for the protective effect of C1P against HAPE, specifically, through stabilizing circadian rhythms and maintaining mitochondrial dynamics. Exogenous C1P therapy may be a promising strategy for treating HAPE. Our findings also highlight the importance of the circadian rhythm and mitochondrial dynamics in the pathogenesis of HAPE, suggesting that targeting these pathways may be a potential therapeutic approach for this condition.