A Homoeostatic Switch Causing Glycerol-3-phosphate and Phosphoethanolamine Accumulation Triggers Senescence by Rewiring Lipid Metabolism

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2024 Feb 26

PMID 38409325

Authors

Khaled Tighanimine

Jose Americo Nabuco Leva Ferreira Freitas

Ivan Nemazanyy

Alexia Bankole

Delphine Benarroch-Popivker

Susanne Brodesser

Gregory Dore

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

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype.

Joung J, Heo Y, Kim Y, Kim J, Choi H, Jeon T Nat Commun. 2025; 16(1):1696.

PMID: 39962062 PMC: 11833096. DOI: 10.1038/s41467-025-56929-0.

Differential transcriptomic profiling of lipid metabolism and collagen remodeling in fast- and slow-twitch skeletal muscles in aging.

Liu Y, Xia G, Zhu S, Shi Y, Huang X, Wu J FASEB J. 2025; 39(2):e70335.

PMID: 39831549 PMC: 11744740. DOI: 10.1096/fj.202402294R.

Assembly and biological functions of metal-biomolecule network nanoparticles formed by metal-phosphonate coordination.

Xu W, Lin Z, Kim C, Wang Z, Wang T, Cortez-Jugo C Sci Adv. 2024; 10(50):eads9542.

PMID: 39671490 PMC: 11641004. DOI: 10.1126/sciadv.ads9542.

Single-Cell Simultaneous Metabolome and Transcriptome Profiling Revealing Metabolite-Gene Correlation Network.

Mao X, Xia D, Xu M, Gao Y, Tong L, Lu C Adv Sci (Weinh). 2024; 12(4):e2411276.

PMID: 39629980 PMC: 11775534. DOI: 10.1002/advs.202411276.

Differential proteomic profiles of exosomes in pediatric and adult adamantinomatous craniopharyngioma cyst fluid.

Chen Y, Wang Z, Huang Q, Wang Y, Yan F, Xiang S Mol Biol Rep. 2024; 51(1):1126.

PMID: 39505756 DOI: 10.1007/s11033-024-10073-y.

References

Gorgoulis V, Adams P, Alimonti A, Bennett D, Bischof O, Bishop C . Cellular Senescence: Defining a Path Forward. Cell. 2019; 179(4):813-827. DOI: 10.1016/j.cell.2019.10.005. View

Wiley C, Campisi J . The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat Metab. 2021; 3(10):1290-1301. PMC: 8889622. DOI: 10.1038/s42255-021-00483-8. View

Neurohr G, Terry R, Lengefeld J, Bonney M, Brittingham G, Moretto F . Excessive Cell Growth Causes Cytoplasm Dilution And Contributes to Senescence. Cell. 2019; 176(5):1083-1097.e18. PMC: 6386581. DOI: 10.1016/j.cell.2019.01.018. View

Dimri G, Lee X, Basile G, Acosta M, Scott G, Roskelley C . A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995; 92(20):9363-7. PMC: 40985. DOI: 10.1073/pnas.92.20.9363. View

Childs B, Gluscevic M, Baker D, Laberge R, Marquess D, Dananberg J . Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. 2017; 16(10):718-735. PMC: 5942225. DOI: 10.1038/nrd.2017.116. View

Zwerschke W, Mazurek S, Stockl P, Hutter E, Eigenbrodt E, Jansen-Durr P . Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence. Biochem J. 2003; 376(Pt 2):403-11. PMC: 1223775. DOI: 10.1042/BJ20030816. View

Unterluggauer H, Mazurek S, Lener B, Hutter E, Eigenbrodt E, Zwerschke W . Premature senescence of human endothelial cells induced by inhibition of glutaminase. Biogerontology. 2008; 9(4):247-59. DOI: 10.1007/s10522-008-9134-x. View

Flor A, Wolfgeher D, Wu D, Kron S . A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence. Cell Death Discov. 2017; 3:17075. PMC: 5661608. DOI: 10.1038/cddiscovery.2017.75. View

Johmura Y, Yamanaka T, Omori S, Wang T, Sugiura Y, Matsumoto M . Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science. 2021; 371(6526):265-270. DOI: 10.1126/science.abb5916. View

10.

Quijano C, Cao L, Fergusson M, Romero H, Liu J, Gutkind S . Oncogene-induced senescence results in marked metabolic and bioenergetic alterations. Cell Cycle. 2012; 11(7):1383-92. PMC: 3350879. DOI: 10.4161/cc.19800. View

11.

Ogrodnik M, Zhu Y, Langhi L, Tchkonia T, Kruger P, Fielder E . Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis. Cell Metab. 2019; 29(5):1233. PMC: 6509279. DOI: 10.1016/j.cmet.2019.01.013. View

12.

Wiley C, Velarde M, Lecot P, Liu S, Sarnoski E, Freund A . Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype. Cell Metab. 2015; 23(2):303-14. PMC: 4749409. DOI: 10.1016/j.cmet.2015.11.011. View

13.

Marschallinger J, Iram T, Zardeneta M, Lee S, Lehallier B, Haney M . Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. 2020; 23(2):194-208. PMC: 7595134. DOI: 10.1038/s41593-019-0566-1. View

14.

Saitou M, Lizardo D, Taskent R, Millner A, Gokcumen O, Atilla-Gokcumen G . An evolutionary transcriptomics approach links CD36 to membrane remodeling in replicative senescence. Mol Omics. 2018; 14(4):237-246. DOI: 10.1039/c8mo00099a. View

15.

Fafian-Labora J, Carpintero-Fernandez P, Jordan S, Shikh-Bahaei T, Abdullah S, Mahenthiran M . FASN activity is important for the initial stages of the induction of senescence. Cell Death Dis. 2019; 10(4):318. PMC: 6453932. DOI: 10.1038/s41419-019-1550-0. View

16.

Kim W, Deik A, Gonzalez C, Gonzalez M, Fu F, Ferrari M . Polyunsaturated Fatty Acid Desaturation Is a Mechanism for Glycolytic NAD Recycling. Cell Metab. 2019; 29(4):856-870.e7. PMC: 6447447. DOI: 10.1016/j.cmet.2018.12.023. View

17.

Romani P, Brian I, Santinon G, Pocaterra A, Audano M, Pedretti S . Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP. Nat Cell Biol. 2019; 21(3):338-347. DOI: 10.1038/s41556-018-0270-5. View

18.

Martinez-Zamudio R, Roux P, de Freitas J, Robinson L, Dore G, Sun B . AP-1 imprints a reversible transcriptional programme of senescent cells. Nat Cell Biol. 2020; 22(7):842-855. PMC: 7899185. DOI: 10.1038/s41556-020-0529-5. View

19.

Hernandez-Segura A, de Jong T, Melov S, Guryev V, Campisi J, Demaria M . Unmasking Transcriptional Heterogeneity in Senescent Cells. Curr Biol. 2017; 27(17):2652-2660.e4. PMC: 5788810. DOI: 10.1016/j.cub.2017.07.033. View

20.

Basisty N, Kale A, Jeon O, Kuehnemann C, Payne T, Rao C . A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 2020; 18(1):e3000599. PMC: 6964821. DOI: 10.1371/journal.pbio.3000599. View