Glycerol-3-phosphate and Phosphoethanolamine homeostatic switch triggers senescence by rewiring lipid metabolism I. Glycerol-3-phosphate and Phosphoethanolamine homeostatic switch triggers senescence by rewiring lipid metabolism I

Cellular senescence impacts many physiological and pathological processes. A durable cell cycle arrest, inflammatory secretory phenotype, and metabolic reprogramming characterize it. Identifying common and specific metabolic liabilities in senescence provide novel inroads to exploit senescence targeting for health benefits. Here, we use dynamic transcriptome and metabolome profiling in different senescence subtypes to reveal common and specific metabolic signatures. Specifically, we pinpoint the homeostatic switch of glycerol-3-phosphate (G3P) and phosphoethanolamine (PEtn) accumulation, intimately linking lipid metabolism to the senescence gene expression program. Mechanistically, p53-dependent glycerol kinase (GK) activation and post-translational inactivation of Phosphate Cytidylyltransferase 2- Ethanolamine (PCYT2) regulate this metabolic switch, which is senogenic. Conversely, G3P phosphatase (G3PP) and Ethanolamine-Phosphate Phospho-Lyase (ETNPPL)-based scavenging of G3P and PEtn is senomorphic. Collectively, our study ties the G3P-PEtn homeostatic switch to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential, novel therapeutic avenue for senescence targeting in pathophysiology. Overall design: We performed time-series gene expression profiling analysis in normal, human diploid fibroblasts (strain WI38) exposed to diverse forms of senescence-inducing stress including hyper-active RAS oncogene, replicative exhaustion (RS), and DNA damage (etoposide, i.e., DDIS). We confirmed these results in additional senescence models: SkMC human primary myoblasts undergoing RAS-OIS. Source code and additional data accessible at: https://zenodo.org/records/8199751

细胞衰老（cellular senescence）可影响诸多生理与病理过程，其典型特征为持久的细胞周期阻滞、炎性分泌表型及代谢重编程。识别衰老过程中共通与特异的代谢易感性，可为靶向衰老以获取健康益处提供全新切入点。本研究针对不同衰老亚型开展动态转录组（transcriptome）与代谢组（metabolome）分析，揭示了共通与特异的代谢特征。具体而言，我们精准定位了甘油-3-磷酸（glycerol-3-phosphate, G3P）与磷酸乙醇胺（phosphoethanolamine, PEtn）积累的稳态转换，将脂质代谢与衰老基因表达程序紧密关联。从机制上看，p53依赖的甘油激酶（glycerol kinase, GK）激活与磷酸胞苷转移酶2-乙醇胺（Phosphate Cytidylyltransferase 2- Ethanolamine, PCYT2）的翻译后失活，调控了这一致衰老性的代谢转换。反之，通过甘油-3-磷酸磷酸酶（G3P phosphatase, G3PP）与乙醇胺-磷酸磷酸裂解酶（Ethanolamine-Phosphate Phospho-Lyase, ETNPPL）介导的G3P和PEtn清除，则具有促衰老表型。综上，本研究将G3P-PEtn稳态转换与衰老细胞内脂滴生成及磷脂通量调控相联系，为病理生理过程中靶向衰老的新型治疗策略提供了潜在可能。
总体设计：本研究对暴露于多种衰老诱导应激的正常人类二倍体成纤维细胞（株系WI38）开展了时序基因表达谱分析，所涉应激包括活化的RAS癌基因、复制性耗竭（RS）以及DNA损伤（依托泊苷诱导，即DDIS）。我们还在额外的衰老模型中验证了上述结果：经RAS-OIS处理的人类原代骨骼肌成肌细胞（SkMC）。
源代码与补充数据可访问：https://zenodo.org/records/8199751