RESUMEN
Cellular senescence affects many physiological and pathological processes and is characterized by durable cell cycle arrest, an inflammatory secretory phenotype and metabolic reprogramming. Here, by using dynamic transcriptome and metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homoeostatic switch that results in glycerol-3-phosphate (G3P) and phosphoethanolamine (pEtN) accumulation links lipid metabolism to the senescence gene expression programme. Mechanistically, p53-dependent glycerol kinase activation and post-translational inactivation of phosphate cytidylyltransferase 2, ethanolamine regulate this metabolic switch, which promotes triglyceride accumulation in lipid droplets and induces the senescence gene expression programme. Conversely, G3P phosphatase and ethanolamine-phosphate phospho-lyase-based scavenging of G3P and pEtN acts in a senomorphic way by reducing G3P and pEtN accumulation. Collectively, our study ties G3P and pEtN accumulation to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential therapeutic avenue for targeting senescence and related pathophysiology.
Asunto(s)
Glicerol , Glicerofosfatos , Metabolismo de los Lípidos , Humanos , Glicerol/metabolismo , Etanolaminas , FosfatosRESUMEN
Many cellular stresses induce cellular senescence and the irreversible arrest of cell proliferation in different cell types. Although blocked in their capacity to divide, senescent cells are metabolically active and are characterized by a different metabolic phenotype as compared to non-senescent cells. Changes observed in senescent cells depend from the cell type and lead to an adaptative flexibility in the type of metabolism. This metabolic reprogramming is needed to cope with survival and with the energetic demands of the senescent program that include the increased secretion of senescence-associated secretory phenotype factors.