Protein & Cell >

2023 , Vol. 14 >Issue 3: 202 - 216

DOI: https://doi.org/10.1093/procel/pwac037

RESEARCH ARTICLE

4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

  • Yifang He 1,4 ,
  • Qianzhao Ji 1,4 ,
  • Zeming Wu 1,3,12 ,
  • Yusheng Cai 1,3,12 ,
  • Jian Yin 1,4 ,
  • Yiyuan Zhang 3,8 ,
  • Sheng Zhang 4,9 ,
  • Xiaoqian Liu 2,3,12 ,
  • Weiqi Zhang 4,6,7,10,11,12 ,
  • Guang-Hui Liu , 1,3,4,5,12 ,
  • Si Wang , 5,10,11 ,
  • Moshi Song , 1,3,4,11,12 ,
  • Jing Qu , 2,3,4,12
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  • 1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 2. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 3. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
  • 4. University of Chinese Academy of Sciences, Beijing 100049, China
  • 5. Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
  • 6. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
  • 7. China National Center for Bioinformation, Beijing 100101, China
  • 8. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
  • 9. State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology(Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
  • 10. Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
  • 11. The Fifth People's Hospital of Chongqing, Chongqing 400062, China
  • 12. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
ghliu@ioz.ac.cn (G.-H. Liu)
wangsi@xwh.ccmu.edu.cn (S. Wang)
songmoshi@ioz.ac.cn (M. Song)
qujing@ioz.ac.cn (J. Qu)

Received date: 20 Apr 2022

Accepted date: 22 May 2022

Copyright

2022 The Author(s) 2022. Published by Oxford University Press on behalf of Higher Education Press.
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Abstract

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1- deficient hMSCs as well as in physiologically aged hMSCs. These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.

Key words： 4E-BP1; mitochondria; aging

Cite this article

Yifang He , Qianzhao Ji , Zeming Wu , Yusheng Cai , Jian Yin , Yiyuan Zhang , Sheng Zhang , Xiaoqian Liu , Weiqi Zhang , Guang-Hui Liu , Si Wang , Moshi Song , Jing Qu . 4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis[J]. Protein & Cell, 2023 , 14(3) : 202 -216 . DOI: 10.1093/procel/pwac037

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