A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism

• DOI: 10.1038/s42255-023-00972-y
• Publication Date: 2024-02-27T00:02:39Z
• Authors: Khaled Tighanimine; José Américo Nabu...; Ivan Nemazanyy; Alexia Bankolé; Delphine Benarroc...; Susanne Brodesser; Gregory Doré; Lucas Robinson; Paule Benit; Sophia Ladraa; Yara Bou Saada; Bertrand Friguet; Philippe Bertolino; David Bernard; Guillaume Canaud; Pierre Rustin; Eric Gilson; Oliver Bischof; Stefano Fumagalli; Mario Pende
• Keywords: Senescence; Metabolome; Lipid droplet

Abstract Cellular senescence affects many physiological and pathological processes is characterized by durable cell cycle arrest, an inflammatory secretory phenotype metabolic reprogramming. Here, using dynamic transcriptome metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homoeostatic switch results glycerol-3-phosphate (G3P) phosphoethanolamine (pEtN) accumulation links lipid metabolism to the gene expression programme. Mechanistically, p53-dependent glycerol kinase activation post-translational inactivation phosphate cytidylyltransferase 2, ethanolamine regulate this switch, which promotes triglyceride droplets induces Conversely, G3P phosphatase ethanolamine-phosphate phospho-lyase-based scavenging pEtN acts senomorphic way reducing accumulation. Collectively, our study ties controlling droplet biogenesis phospholipid flux senescent cells, providing potential therapeutic avenue for targeting related pathophysiology.