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

doi:10.1093/procel/pwac037

Protein Cell

2023, Vol. 14

Issue (3) : 202-216 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(

)

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

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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.

Keywords 4E-BP1 mitochondria aging

Corresponding Author(s): Guang-Hui Liu,Si Wang,Moshi Song,Jing Qu

Issue Date: 17 April 2023

Cite this article:

Yifang He,Qianzhao Ji,Zeming Wu, et al. 4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis[J]. Protein Cell, 2023, 14(3): 202-216.

URL:

https://academic.hep.com.cn/pac/EN/10.1093/procel/pwac037
https://academic.hep.com.cn/pac/EN/Y2023/V14/I3/202

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