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

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

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

Author: Yifang HE ¹ ; Qianzhao JI ¹ ; Zeming WU ¹ ; Yusheng CAI ¹ ; Jian YIN ¹ ; Yiyuan ZHANG ² ; Sheng ZHANG ³ ; Xiaoqian LIU ⁴ ; Weiqi ZHANG ³ ; Guang-Hui LIU ¹ ; Si WANG ⁵ ; Moshi SONG ¹ ; Jing QU ⁴
Author Information

1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
2. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
3. University of Chinese Academy of Sciences, Beijing 100049, China.
4. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, 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.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: 4E-BP1; aging; mitochondria
MeSH: Mesenchymal Stem Cells/physiology*; Cellular Senescence; Homeostasis; Cell Cycle Proteins/metabolism*; Adaptor Proteins, Signal Transducing/metabolism*; Mitochondria/metabolism*; Electron Transport Complex III/metabolism*; Humans; Cells, Cultured
From: Protein & Cell 2023;14(3):202-216
CountryChina
Language:English
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 f indings 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.