1. 4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis
- Author
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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, and Jing Qu
- Subjects
Drug Discovery ,Cell Biology ,Biochemistry ,Biotechnology - 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 the 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.
- Published
- 2022