Abstract
RIPK1 is a crucial regulator of cell death and survival. Ripk1 deficiency promotes mouse survival in the prenatal period while inhibits survival in the early postnatal period without a clear mechanism. Metabolism regulation and autophagy are critical to neonatal survival from severe starvation at birth. However, the mechanism by which RIPK1 regulates starvation resistance and survival remains unclear. Here, we address this question by discovering the metabolic regulatory role of RIPK1. First, metabolomics analysis reveals that Ripk1 deficiency specifically increases aspartate levels in both mouse neonates and mammalian cells under starvation conditions. Increased aspartate in Ripk1−/− cells enhances the TCA flux and ATP production. The energy imbalance causes defective autophagy induction by inhibiting the AMPK/ULK1 pathway. Transcriptional analyses demonstrate that Ripk1−/− deficiency downregulates gene expression in aspartate catabolism by inactivating SP1. To summarize, this study reveals that RIPK1 serves as a metabolic regulator responsible for starvation resistance.
Highlights
Receptor-interacting protein kinase-1 (RIPK1) is a crucial regulator of cell death and survival
Similar to Ripk1−/− mice, genetic ablation of autophagy machines, such as Atg[5] in mice, causes postnatal lethality with a significantly decreased amino acid pool[13]. This suggests that RIPK1 may serve as a regulator that is responsible for starvation resistance at birth and supports neonatal survival
Ripk1−/− mouse neonates died in a short time without milk feeding after delivery (Fig. 1c), and the survival time was slightly prolonged with milk feeding (Fig. 1d), suggesting that Ripk1−/− neonates may die due to defects in starvation resistance
Summary
RIPK1 is a crucial regulator of cell death and survival. Ripk[1] deficiency promotes mouse survival in the prenatal period while inhibits survival in the early postnatal period without a clear mechanism. Under CHX treatment and EBSS starvation conditions, Ripk[1] deficiency still inhibited cell survival significantly (Fig. 1a, b). These results suggest that the increased aspartate levels in Ripk1−/− cells underlie the mechanism of defective starvation-induced autophagy.
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