4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis
Received date: 20 Apr 2022
Accepted date: 22 May 2022
Copyright
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
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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