1. Academic Validation
  2. Trimethylamine N-oxide (TMAO) treatment triggers premature ovarian insufficiency (POI) via the activation of mitochondrial pathway apoptosis in granulosa cells

Trimethylamine N-oxide (TMAO) treatment triggers premature ovarian insufficiency (POI) via the activation of mitochondrial pathway apoptosis in granulosa cells

  • Free Radic Biol Med. 2025 Mar 6:232:214-230. doi: 10.1016/j.freeradbiomed.2025.03.007.
Yuanhong Peng 1 Yingjin Wang 2 Jiangshan Hu 2 Zhijie Wang 3 Yue Liu 4 Zhide Ding 5
Affiliations

Affiliations

  • 1 Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 2 Department of Obstetrics and Gynecology, Shanghai Eighth People's Hospital, Shanghai, 200235, China.
  • 3 Department of Obstetrics and Gynecology, Shanghai Eighth People's Hospital, Shanghai, 200235, China. Electronic address: wangzhj1968@sina.com.
  • 4 Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: liuyue@shsmu.edu.cn.
  • 5 Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: zding@shsmu.edu.cn.
Abstract

Premature ovarian insufficiency (POI) is characterized by follicular development failure or follicular dysplasia, therefore causing the lack of normal ovarian function before 40 years of age. Trimethylamine N-oxide (TMAO) is a metabolite of high choline diet rich in red meat and directly associated with gut microbiota. Correlation of TMAO level with female fertility decline has been shown; however, its mechanism is largely unknown. To unveil the mechanism by which TMAO affects female reproductive function, we established a TMAO-treated mouse model which exhibited the pathological manifestations of POI including increased follicle-stimulating hormone and luteinizing hormone levels, decreased estradiol and anti-Müllerian hormone levels, reduced growing and mature follicles, increased atretic follicles, and decreased fertility. Meanwhile, these mice showed an increased Apoptosis ratio and damaged mitochondrial function in granulosa cells, the nursing and supporting cells for oocyte development. Moreover, TMAO treatment significantly elevated oxidative stress and reduced antioxidative capacity in granulosa cells, whereas the Antioxidants N-acetylcysteine alleviated such detriment. Mechanism investigation demonstrated that TMAO treatment up-regulated Phosphatase and tensin homolog expression levels in granulosa cells, thereby inhibiting the phosphorylation of Akt and subsequently causing high expression of BCL-2-associated X protein, a key molecule in the mitochondria pathway, leading to increased cell Apoptosis. Our findings documented the pathological mechanism of TMAO-induced POI, which may provide a potential target for curing POI clinically.

Keywords

Apoptosis; Granulosa cells; Mitochondrial pathway; N-acetylcysteine; Premature ovarian insufficiency (POI); Trimethylamine N-oxide (TMAO); oxidative stress.

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