Genistein mitigates senescence of bone marrow mesenchymal stem cells via ERRα-mediated mitochondrial biogenesis and mitophagy in ovariectomized rats

Mengyu Li; Yejia Yu; Ke Xue; Jiayi Li; Geehun Son; Jiajia Wang; Wentao Qian; Shaoyi Wang; Jiawei Zheng; Chi Yang; Jing Ge

doi:10.1016/j.redox.2023.102649

Genistein mitigates senescence of bone marrow mesenchymal stem cells via ERRα-mediated mitochondrial biogenesis and mitophagy in ovariectomized rats

Redox Biol. 2023 May:61:102649. doi: 10.1016/j.redox.2023.102649. Epub 2023 Feb 27.

Authors

Mengyu Li¹, Yejia Yu¹, Ke Xue², Jiayi Li¹, Geehun Son¹, Jiajia Wang¹, Wentao Qian¹, Shaoyi Wang¹, Jiawei Zheng³, Chi Yang⁴, Jing Ge⁵

Affiliations

¹ Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
² Department of Pastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Oromaxillofacial Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
⁴ Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China. Electronic address: yangchi63@hotmail.com.
⁵ Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China. Electronic address: 2044328567@qq.com.

Abstract

Senescence of bone marrow mesenchymal stem cells (BMMSCs) induced by chronic oxidative stress is an important factor contributes to the postmenopausal osteoporosis (PMOP). Mitochondrial quality control takes a pivotal role in regulating oxidative stress and cell senescence. Genistein is a major isoflavone in soy products, which is best known for its ability to inhibit bone loss in both postmenopausal women and ovariectomized (OVX) rodents. Here we show that OVX-BMMSCs displayed premature senescence, elevated reactive oxygen species (ROS) level and mitochondria dysfunction, while genistein rescued these phenotypes. Using network pharmacology and molecular docking, we identified estrogen-related receptor α (ERRα) as the potential target of genistein. Knockdown of ERRα greatly abolished the anti-senescence effect of genistein on OVX-BMMSCs. Further, the mitochondrial biogenesis and mitophagy induced by genistein were inhibited by ERRα knockdown in OVX-BMMSCs. In vivo, genistein inhibited trabecular bone loss and p16^INK4a expression, upregulated sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor gamma coactivator one alpha (PGC1α) expression in the trabecular bone area of proximal tibia in OVX rats. Together, this study revealed that genistein ameliorates senescence of OVX-BMMSCs through ERRα-mediated mitochondrial biogenesis and mitophagy, which provided a molecular basis for advancement and development of therapeutic strategies against PMOP.

Keywords: Estrogen-related receptor α; Mesenchymal stem cells; Mitophagy; Osteoporosis; Senescence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cellular Senescence
ERRalpha Estrogen-Related Receptor
Female
Genistein* / metabolism
Genistein* / pharmacology
Mesenchymal Stem Cells* / metabolism
Mitophagy
Molecular Docking Simulation
Organelle Biogenesis
Ovariectomy
Rats

Substances

Genistein