![]() ![]() RIPK1 is essential for survival under starvation conditions by activating autophagy The results demonstrate that RIPK1 is a nutrient stress sensor and metabolic regulator that is critical to maintaining metabolic homeostasis under starvation conditions. Then, through combined metabolomics, RNA-sequencing (RNA-seq), and mechanistic studies, we reveal that Ripk1 deficiency modulates aspartate catabolism and disrupts metabolic homeostasis, which inactivates starvation-induced autophagy. In particular, aspartate has been reported as an essential metabolite for cell growth 21, 22. For example, the concentrations of amino acids in neonatal Atg5 −/− mice are significantly lower than those in wild-type (WT) mice 13. Amino acids play an important role in regulating various cellular processes, including autophagy 20. Then, we employe metabolomics to profile the metabolic changes responding to Ripk1 deficiency and discovere the dysregulation of aspartate metabolism in Ripk1-deficient conditions. In this study, we first discovere that RIPK1 is required for cell survival under starvation conditions but not under normal conditions. Thus, we hypothesized that RIPK1 may also play a vital role in starvation resistance by regulating cellular metabolism. ![]() For example, the loss of RIPK1 in lung cancer cells impairs mitochondrial oxidative phosphorylation and accelerates glycolysis 19. Emerging evidence has delineated the regulatory role of RIPK1 in metabolism. RIPK1 has been reported as a sensor of various stresses 17, 18. Given that metabolic balance is critical to starvation resistance, how cells sense starvation and reprogram metabolism is still elusive. Metabolic alteration plays a pivotal role in the response to starvation, which enables cell survival and maintains organismal function 14, 15, 16. This suggests that RIPK1 may serve as a regulator that is responsible for starvation resistance at birth and supports neonatal survival. Similar to Ripk1 −/− mice, genetic ablation of autophagy machines, such as Atg5 in mice, also causes postnatal lethality with a significantly decreased amino acid pool 13. Neonates adapt to this severe starvation circumstance by activating autophagy to maintain the supply of amino acids and metabolic homeostasis 13. At birth, the transplacental nutrient supply is suddenly interrupted, and neonates face severe nutritional deficiency. This demonstrates that RIPK1 specifically promotes survival in the neonatal period. Although Ripk1 knockout rescues the prenatal death of Fadd −/− mice, Ripk1 −/− Fadd −/− mice still die in a short time after birth 9. However, Ripk1 −/− mice appear almost normally in the prenatal period while exhibit postnatal lethality with extensive cell death within 1–3 days after birth 8, 9, 10, 11, 12. ![]() In mice, genetic ablation of cell death-related genes mostly leads to prenatal death or embryonic defects (e.g., Fadd −/− mice) 7. Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of cell survival and death 1, 2, 3, 4 and mediates FADD/caspase-8-dependent apoptosis and RIPK3-dependent necrosis 5, 6. To summarize, this study reveals that RIPK1 serves as a metabolic regulator responsible for starvation resistance. ![]() Transcriptional analyses demonstrate that Ripk1 − /− deficiency downregulates gene expression in aspartate catabolism by inactivating SP1. The energy imbalance causes defective autophagy induction by inhibiting the AMPK/ULK1 pathway. Increased aspartate in Ripk1 − /− cells enhances the TCA flux and ATP production. First, metabolomics analysis reveals that Ripk1 deficiency specifically increases aspartate levels in both mouse neonates and mammalian cells under starvation conditions. Here, we address this question by discovering the metabolic regulatory role of RIPK1. However, the mechanism by which RIPK1 regulates starvation resistance and survival remains unclear. Metabolism regulation and autophagy are critical to neonatal survival from severe starvation at birth. Ripk1 deficiency promotes mouse survival in the prenatal period while inhibits survival in the early postnatal period without a clear mechanism. RIPK1 is a crucial regulator of cell death and survival. ![]()
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