Journal
PROTEIN & CELL
Volume 14, Issue 3, Pages 202-216Publisher
OXFORD UNIV PRESS
DOI: 10.1093/procel/pwac037
Keywords
4E-BP1; mitochondria; aging
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Research shows that the expression of 4E-BP1 decreases during the senescence of human stem cells. The absence of 4E-BP1 leads to abnormal mitochondrial respiration and increased production of reactive oxygen species, resulting in accelerated cellular senescence. However, ectopic expression of 4E-BP1 can alleviate mitochondrial abnormalities and cellular senescence, maintaining mitochondrial homeostasis. This study provides a new potential target for counteracting human stem cell senescence.
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.
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