Fut2 Deficiency Promotes Intestinal Stem Cell Aging by Damaging Mitochondrial Functions via Down-Regulatingα1,2-Fucosylation of Asah2 and Npc1  

作　　者：Caihan Duan Zhe Wang Junhao Wu Chen Tan Feifei Fang Wei Qian Chaoqun Han Xiaohua Hou 

机构地区：[1]Division of Gastroenterology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China

出　　处：《Research》2024年第4期545-561,共17页研究(英文)

基　　金：supported by the National Natural Science Foundation of China(grant nos.92268108,82170570,and 81974062).

摘　　要：Fut2-mediatedα1,2-fucosylation is important for gut homeostasis,including the intestinal stem cell(ISC).The stemness of ISC declines with age,and aging-associated ISC dysfunction is closely related to many age-related intestinal diseases.We previously found intestinal epithelial dysfunction in some aged Fut2 knockout mice.However,how Fut2-mediatedα1,2-fucosylation affects ISC aging is still unknown.On this basis,the herein study aims to investigate the role of Fut2-mediatedα1,2-fucosylation in ISC aging.Aging models in ISC-specific Fut2 knockout mice were established.ISCs were isolated for proteomics and N-glycoproteomics analysis.ISC functions and mitochondrial functions were examined in mice and organoids.Ulex europaeus agglutinin I chromatography and site-directed mutagenesis were used to validate the key target fucosylated proteins of Fut2.As a result,Fut2 knockout impaired ISC stemness and promoted aging marker expression in aged mice.Proteomics analysis indicated mitochondrial dysfunction in Fut2 knockout ISC.More injured mitochondria,elevated levels of reactive oxygen species,and decreased levels of adenosine 5′-triphosphate(ATP)in Fut2 knockout ISC were found.Moreover,respiratory chain complex impairment and mitophagy dysfunction in Fut2 knockout ISC were further noted.Finally,Fut2 was demonstrated to regulate mitochondrial functions mainly by regulating theα1,2-fucosylation of N-acyl sphingosine amidohydrolase 2(Asah2)and Niemann–Pick type C intracellular cholesterol transporter 1(Npc1).In conclusion,this study demonstrated the substantial role of Fut2 in regulating ISC functions during aging by affecting mitochondrial function.These findings provide novel insights into the molecular mechanisms of ISC aging and therapeutic strategies for age-related intestinal diseases.

关 键 词：IMPAIRED AGING ELEVATED 

分 类 号：R57[医药卫生—消化系统]