Tobacco toxins trigger bone marrow mesenchymal stem cells aging by inhibiting mitophagy

作者全名：Xiang, Kai; Ren, Mingxing; Liu, Fengyi; Li, Yuzhou; He, Ping; Gong, Xuerui; Chen, Tao; Wu, Tianli; Huang, Ziyu; She, Hui; Liu, Kehao; Jing, Zheng; Yang, Sheng

作者地址：[Xiang, Kai; Ren, Mingxing; Liu, Fengyi; Li, Yuzhou; He, Ping; Gong, Xuerui; Chen, Tao; Wu, Tianli; Huang, Ziyu; She, Hui; Liu, Kehao; Jing, Zheng; Yang, Sheng] Chongqing Med Univ, Stomatol Hosp, Chongqing, Peoples R China; [Liu, Fengyi; Li, Yuzhou; He, Ping; Jing, Zheng; Yang, Sheng] Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing, Peoples R China; [Liu, Fengyi; Li, Yuzhou; He, Ping; Jing, Zheng; Yang, Sheng] Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing, Peoples R China; [Jing, Zheng; Yang, Sheng] 426 Songshi North Rd,, Chongqing 401147, Peoples R China

通信作者：Jing, Z; Yang, S (通讯作者)，426 Songshi North Rd,, Chongqing 401147, Peoples R China.

来源：ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY

ESI学科分类：ENVIRONMENT/ECOLOGY

WOS号：WOS:001235392100001

JCR分区：Q1

影响因子：6.2

年份：2024

卷号：277

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Cigarette smoke extract; Mitophagy; Bone marrow mesenchymal stem cells; Osteoporosis; Aging

摘要：Smoking disrupts bone homeostasis and serves as an independent risk factor for the development and progression of osteoporosis. Tobacco toxins inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), promote BMSCs aging and exhaustion, but the specific mechanisms are not yet fully understood. Herein, we successfully established a smoking-related osteoporosis (SROP) model in rats and mice through intraperitoneal injection of cigarette smoke extract (CSE), which significantly reduced bone density and induced aging and inhibited osteogenic differentiation of BMSCs both in vivo and in vitro. Bioinformatics analysis and in vitro experiments confirmed that CSE disrupts mitochondrial homeostasis through oxidative stress and inhibition of mitophagy. Furthermore, we discovered that CSE induced BMSCs aging by upregulating phosphorylated AKT, which in turn inhibited the expression of FOXO3a and the Pink1/Parkin pathway, leading to the suppression of mitophagy and the accumulation of damaged mitochondria. MitoQ, a mitochondrialtargeted antioxidant and mitophagy agonist, was effective in reducing CSE-induced mitochondrial oxidative stress, promoting mitophagy, significantly downregulating the expression of aging markers in BMSCs, restoring osteogenic differentiation, and alleviating bone loss and autophagy levels in CSE-exposed mice. In summary, our results suggest that BMSCs aging caused by the inhibition of mitophagy through the AKT/FOXO3a/Pink1/Parkin axis is a key mechanism in smoking-related osteoporosis.

基金机构：National Natural Science Foundation of China [U23A20447, 82171010, 82270962, 82301034]; Natural Science Foundation of Chongqing, China [cstc2021jcyj-jqX0028, cstc2020jcyj-msxmX0131, CSTB2023NSCQ-BHX0072]; CQMU Program for Youth Innovation in Future Medicine [W0079]; Project of Chongqing Medical University Graduate Tutor Team [cqmudstd202203]

基金资助正文：This work was supported by National Natural Science Foundation of China (Grant No. U23A20447, 82171010, 82270962, 82301034) ; the Natural Science Foundation of Chongqing, China (Grant No. cstc2021jcyj-jqX0028, cstc2020jcyj-msxmX0131, CSTB2023NSCQ-BHX0072) ; CQMU Program for Youth Innovation in Future Medicine (No. W0079) ; Project of Chongqing Medical University Graduate Tutor Team (cqmudstd202203) .