MAVS Antagonizes Human Stem Cell Senescence as a Mitochondrial Stabilizer  

作　　者：Cui Wang Kuan Yang Xiaoqian Liu Si Wang Moshi Song Juan Carlos Izpisua Belimonte Jing Qu Guang-Hui Liu Weiqi Zhang 

机构地区：[1]CAS Key Laboratory of Genomic and Precision Medicine,Beijng Institute of Genomics,Chinese Academy of Sciences and China National Center for Bioinformation,Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Sino-Danish College,University of Chinese Academy of Sciences,Beijing 101408,China [4]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China [5]Institute for Stem Cell and Regeneration Chinese Academy of Sciences,Beijing 100101,China [6]Beijing Institute for Stem Cell and Regenerative Medicine,Bejing 100101,China [7]Advanced Innovation Center for Human Brain Protection,National Clinical Research Center for Geriatric Disorders,Xuanwu Hospital Capital Medical University,Beijing 100053,China [8]State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China [9]Altos Labs,Inc.,San Diego,CA 94022,USA

出　　处：《Research》2024年第2期239-257,共19页研究（英文）

基　　金：supported by the National Key Research and Development Program of China(2022YFA1103700,2020YFA0804000,2020YFA0112200,2021YFF1201005,and the STI2030-Major Projects-2021ZD0202400);the National Natural Science Foundation of China(81921006,82125011,92149301,92168201,91949209,92049304,92049116,32121001,82192863,82122024,and 82071588);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16000000);CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012);the Program of the Beijing Natural Science Foundation(Z190019);Youth Innovation Promotion Association of CAS(E1CAZW0401);the Pilot Project for Public Welfare Development and Reform of Beijing-affiliated Medical Research Institutes(11000022T000000461062);the Informatization Plan of Chinese Academy of Sciences(CAS-WX2021SF-0101,CAS-WX2021SF-0301,and CAS-WX2022SDC-XK14);Young Elite Scientists Sponsorship Program by CAST(YESS20200012);the New Cornerstone Science Foundation through the XPLORER PRIZE(2021-1045);the Excellent Young Talents Program of Capital Medical University(12300927);the Excellent Young Talents Training Program for the Construction of Beijing Municipal University Teacher Team(BPHR202203105).

摘　　要：Mitochondrial dysfunction is a hallmark feature of cellular senescence and organ aging.Here,we asked whether the mitochondrial antiviral signaling protein(MAVS),which is essential for driving antiviral response,also regulates human stem cell senescence.To answer this question,we used CRISPR/Cas9-mediated gene editing and directed differentiation techniques to generate various MAVS-knockout human stem cell models.We found that human mesenchymal stem cells(hMSCs)were sensitive to MAVS deficiency,as manifested by accelerated senescence phenotypes.We uncovered that the role of MAVS in maintaining mitochondrial structural integrity and functional homeostasis depends on its interaction with the guanosine triphosphatase optic atrophy type 1(OPA1).Depletion of MAVS or OPA1 led to the dysfunction of mitochondria and cellular senescence,whereas replenishment of MAVS or OPA1 in MAVS-knockout hMSCs alleviated mitochondrial defects and premature senescence phenotypes.Taken together,our data underscore an uncanonical role of MAVS in safeguarding mitochondrial homeostasis and antagonizing human stem cell senescence.

关 键 词：CRISPR/Cas9 HOMEOSTASIS MITOCHONDRIAL 

分 类 号：R32[医药卫生—人体解剖和组织胚胎学]