Cellular senescence is deeply involved in physiological homeostasis,development,tissue repair,aging,and diseases.Senescent cells(SnCs)accumulate in aged tissues and exert deleterious effects by secreting proinflammato...Cellular senescence is deeply involved in physiological homeostasis,development,tissue repair,aging,and diseases.Senescent cells(SnCs)accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases.We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis,whose byproduct,lactate,promotes this binding in a noncell autonomous manner.The pseudo-Warburg effect of SnCs with enhanced PPP(pentose phosphate pathway)activity is maintained by HIF-2αphosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes,creating a vicious cycle reprogramming the glycolytic pathway in SnCs.HIF-2αalso activates FoxM1 expression,which transcriptionally suppresses proapoptotic profiles,including BIM,and upregulates DNA repair machineries in SnCs.FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes.Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis.Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models.Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.展开更多
基金supported in part by grants from the MEXT/JSPS(Grants No.26310103,16K15412,17H04150,18K18451,20K20658,23K27507 and 23H03884 to Hiroshi Kondoh,19K07887 and 22K06221 to T.M.,21K15661 to M.K.,23K27595 to K.O.,20H04116 and 24K02871 to M.S.,20H03583 and 22K1960 to T.S.,17H03574 and 23K21640 to N.O.,JP24H00640 to K.T.)AMED-CREST(JP20gm1210011 to K.T.and JP25gm1710007 to T.S.)+2 种基金the French National Cancer Institute INCA(PLBio No.2018-144 and INCA TABAC 17-007 to D.B.)the GAP fund program,the Incubation Program and IPG-Advance of Kyoto University to Hiroshi KondohThis work was supported by JSPS KAKENHI Grant Number JP 22H04922(AdAMS).
文摘Cellular senescence is deeply involved in physiological homeostasis,development,tissue repair,aging,and diseases.Senescent cells(SnCs)accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases.We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis,whose byproduct,lactate,promotes this binding in a noncell autonomous manner.The pseudo-Warburg effect of SnCs with enhanced PPP(pentose phosphate pathway)activity is maintained by HIF-2αphosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes,creating a vicious cycle reprogramming the glycolytic pathway in SnCs.HIF-2αalso activates FoxM1 expression,which transcriptionally suppresses proapoptotic profiles,including BIM,and upregulates DNA repair machineries in SnCs.FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes.Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis.Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models.Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.
