Quercetin ameliorates diminished ovarian reserve via modulating intestinal BNIP3/dct-1-mediated mitophagy and subsequently activating the ovarian TGF-β signaling pathway.

Diminished ovarian reserve (DOR) is one of the most important reasons for decreasing fertility. Quercetin, a phytochemical, widely exists in food and natural Chinese herbs and can increase female fertility. However, how the phytochemical improves fertility through increasing ovarian reserve remains unclear. The study aims to investigated how quercetin improve ovarian reserve through improving intestinal mitophagy in a DOR mouse and C. elegans model. Tripterygium glycoside/triptolide (TP) were used to establish DOR model in mice and C. elegans. Brood size was used to evaluate fertility of worms. Oogenesis in worms and proportion of follicles in mice were used to evaluate oocyte reserve. Loss-of-functional mutants and fluorescent protein transgene strains were used to evaluate gene function. PCR and RNAi were used to detect gene or protein function. Tissue-specific RNAi knockdown worms and intestine-specific AAV-Bnip3-RNAi knockdown mice were used to study the signaling transduction from intestine to gonad. Quercetin enhanced the fertility in DOR worms by improving the oogenesis, and improved the development and quality of follicles in DOR mice. Quercetin restored mitochondrial function through reducing of mitochondrial-reactive oxygen species (ROS), restoring mitochondrial membrane potential, and enhancing mitophagy in DOR worms. Quercetin increased ovarian reserve in the DOR worms via cooperation of mitophagy downstream dct-1 in gonad and intestine, while also amelioraing intestinal permeability through intestinal dct-1. Notably, dct-1 activation in intestine facilitated the TGF-β signaling pathway in the gonad of DOR worms, which was confirmed in DOR mice. Furthermore, quercetin alleviated intestinal tissue damage by longer villi via BNIP3 (the ortholog of dct-1) in DOR mice. Quercetin upregulated the protein expression of BNIP3 in both the intestine and ovary, and of HIVEP2 (the ortholog of sma-9) in the ovary of DOR mice. Meanwhile, intestine-specific BNIP3 knockdown inhibited the quercetin-induced beneficial effects and HIVEP2 expression in ovary in the DOR mice. Quercetin improved the ovarian reserve through enhancing intestinal BNIP3/dct-1-mediated mitophagy, ameliorating intestinal permeability, and improving ovarian TGF-β signaling pathway.