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Uridine restores oocyte quality and mitigates female reproductive aging by inhibition of ferroptosis in mice

ABSTRACT: Advanced maternal age is a key factor in female infertility, primarily due to declines in ovarian reserve and oocyte quality. However, the metabolic mechanisms underlying reproductive aging remain unclear. Here, we show that uridine levels in the plasma and ovaries of aged mice are significantly reduced compared with young controls. Building on this, we find that uridine supplementation significantly improves meiotic maturation, fertilization, and early embryonic development of aged oocytes, both in vivo and in vitro. Further microtranscriptomic analyses reveal that uridine enhances oocyte quality by inhibiting ferroptosis and enhancing mitochondrial function. Moreover, integrating Limited Proteolysis-Small Molecule Mapping, western blot and siRNA-based functional assays, we identify that uridine binds Poly(rC)-binding protein 1, thereby suppressing ferroptosis and preserving mitochondrial function. Collectively, these findings demonstrate that uridine supplementation improves fertility in aged female mice and provide mechanistic insight into ferroptosis in oocyte aging.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Ovary

SUBMITTER: JING CHEN

LAB HEAD: Jingyue Chen

PROVIDER: PXD075265 | Pride | 2026-03-05

REPOSITORIES: Pride

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			Action	DRS
	checksum.txt	Txt
	ovary_control_1.raw	Raw
	ovary_control_2.raw	Raw
	ovary_control_3.raw	Raw
	ovary_uridine_1.raw	Raw

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Similar Datasets

Uridine restores oocyte quality and mitigates female reproductive aging by inhibition of ferroptosis in mice

Project description:<p>Advanced maternal age is a key factor in female infertility, primarily due to declines in ovarian reserve and oocyte quality. However, the metabolic mechanisms underlying reproductive aging are still poorly understood. Here, we show that uridine levels in the plasma and ovaries of aged mice are significantly reduced compared with young controls. Building on this, we find that uridine supplementation significantly improves meiotic maturation, fertilization, and early embryonic development of aged oocytes, both in vivo and in vitro. Further microtranscriptomic analyses reveal that uridine enhances oocyte quality by inhibiting ferroptosis, enhancing mitochondrial function and removing excessive reactive oxygen species (ROS). Moreover, integrating Limited Proteolysis-Small Molecule Mapping (LiP-SMap), surface plasmon resonance (SPR) analyses and siRNA-based functional assays, we identify that uridine binds Poly(rC)-binding protein 1 (PCBP1), thereby suppressing ferroptosis and preserving mitochondrial function. In conclusion, this study demonstrates that uridine supplementation can effectively improve fertility of aged female mice. Our research also provides important insights into the role of ferroptosis in oocyte aging, thereby advancing our understanding of reproductive aging mechanisms.</p>

2026-03-03 | MTBLS13957 | MetaboLights

Growth hormone supplementation reduces aneuploidy and improves the quality of oocytes by activating ERK1/2 pathway in aged mice

Project description:The decline in oocyte quality is a limiting factor of female fertility; however, strategies to maintain the oocyte quality of aged women are not available. In this study, we showed that growth hormone (GH) supplementation in vivo not only alleviated the decline in oocyte number caused by aging, but also improved the quality and developmental potential of aged oocytes. Strikingly, GH supplementation reduced aneuploidy in aged oocytes. Proteomic analysis indicated that the ERK1/2 pathway was involved in the reduction in aneuploidy rate of aged oocytes, as confirmed both in vivo and in vitro. In addition, JAK2 might be involved in the regulation of ERK1/2 by GH in aged oocytes. Collectively, our findings revealed that GH supplementation protects oocytes from aging-related aneuploidy and enhances the quality of aged oocytes, and could be used to improve the outcome of assisted reproduction in aged women.

2023-07-20 | PXD039147 | Pride

Polyamine metabolite spermidine rejuvenates the oocyte quality by enhancing mitophagy during female reproductive aging

Project description:Advanced age is a primary risk factor for female infertility due to reduced ovarian reserve and declining oocyte quality. However, as an important contributing factor, the role of metabolic regulation during reproductive aging is poorly understood. Here, we applied untargeted metabolomics to identify spermidine as a critical metabolite in ovaries to protect oocytes against aging. In particular, we found that spermidine level was reduced in aged ovaries and supplementation of spermidine promoted follicle development, oocyte maturation, early embryonic development and female fertility of aged mice. By micro-transcriptomic analysis, we further discovered that recovery of oocyte quality by spermidine was mediated by enhancement of mitophagy activity and mitochondrial function in aged mice, and this action mechanism was conserved in porcine oocytes under oxidative stress. Altogether, our findings demonstrate that spermidine supplementation is a potentially effective strategy to ameliorate oocyte quality and reproductive outcome of women at an advanced age.

2023-11-10 | GSE239551 | GEO

Nicotinamide mononucleotide supplementation reverses the declining quality of maternally aged oocytes

Project description:Advanced maternal age, defined as 35 years or older, is associated with a decline in both ovarian reserve and oocyte quality, which leads to the female infertility, pregnancy loss, fetal anomalies, stillbirth, and obstetric complications. At present, the effective approaches to counteract the maternal age-related decay of oocyte quality are still not fully determined. Here, we report that in vivo supplementation of nicotinamide mononucleotide (NMN) efficaciously ameliorates the quality of oocytes from naturally aged mice by recovering nicotinamide adenine dinucleotide (NAD + ) levels in oocytes. NMN supplementation increases the number of antral follicles, ovulated oocytes and matured oocytes from aged mice. Specifically, NMN supplementation maintains the normal spindle/chromosome structure and dynamics of cortical granule component ovastacin to ensure the meiotic competency and fertilization ability of aged oocytes. Moreover, single cell transcriptome analysis shows that the beneficial effect of NMN on the aged oocytes is mediated by the restoration of the mitochondrial function, thereby reducing the accumulated ROS to suppress the occurrence of apoptosis. To sum up, our data reveal that supplementation of NMN is a feasible approach to prevent oocyte quality from advanced maternal age-related deterioration, contributing to improve the reproductive outcome of aged women and the assisted reproductive technology.

2023-07-01 | GSE153920 | GEO

Plat safeguards aged mouse oocytes against programmed cell death through activating the Erk1/2 pathway

Project description:Female reproductive aging is characterized by the decline in oocytes quality and developmental potentials, but the underlying mechanisms remain insufficiently investigated. In this study, we analyze the transcriptomes of individual oocytes from young and aged mice, identifying a distinct group of aged oocytes, which display morphological abnormalities, such as fragmentation and darkened cytoplasm. These defective aged oocytes show a global shrink in gene expression, with yet a notable expression increase in mitochondrial RNA. Further gene expression analysis indicates that these defective oocytes exhibit typical features of programmed cell death (PCD), and functional assays demonstrate that those oocytes are specifically subject to both apoptosis and ferroptosis. Blocking the PCD pathways largely reverses the defective morphology. Interestingly, the expression of tissue-type plasminogen activator (tPA, or Plat) decreases with age, and even becomes undetectable in defective oocytes. Loss of Plat expression in oocytes downregulates Erk1/2 pathway activity, closely resembling the effects observed in Erk1/2 deficiency. Combining with tPA-interactome assay, it is suggested that Plat functions as an upstream regulator of Erk1/2 pathway activity, likely through Erk1/2 phosphorylation. Supplementing exogenous tPA in oocyte cultures reduces defect rate and therefore improves oocyte quality. Collectively, our findings highlight Plat as a pivotal factor in protecting aged mouse oocytes from PCD, with potential implications for developing better clinical strategies to enhance oocyte quality in aging females.

2025-09-13 | GSE281294 | GEO

Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy [HiC GGOH-treatment]

Project description:The mechanisms of aging-related oocyte aneuploidy remain elusive. Hi-C and SMART-seq revealed aging-related decreases in chromosome condensation, particularly for genomic regions proximal to the centromeres, accompanied with disrupted meiosis-associated gene expression in metaphase I (MI) aged oocytes. Further transcriptomic analysis showed that oocyte meiotic maturation was correlated with robust increases in mevalonate (MVA) pathway gene expression in young oocyte-surrounding granulosa cells (GCs), which was largely downregulated in aged GCs. Inhibtion of MVA metabolism in GCs by statins resulted in marked meiotic defects and aneuploidy in young cumulus-oocyte complexes (COCs). Conversely, supplementation with the MVA isoprenoid geranylgeraniol ameliorated meiotic defects and aneuploidy in aged COCs. Meanwhile, geranylgeraniol also activated LHR/EGF signaling in aged GCs and then enhanced the meiosis-associated gene expression in oocytes. Generally, the MVA pathway in GCs is a critical regulator of meiotic maturation and euploidy in oocytes.

2023-02-26 | GSE212860 | GEO

Unlocking Oocyte Potential: L-Asp's Protective Role Against Heat-Induced Meiotic Disruption

Project description:Global warming has made heat stress (HS) an unavoidable challenge in livestock production, significantly impacting animal feed intake, growth, reproduction, and health. Germ cells, including oocytes, are particularly sensitive to HS, with impaired oocyte maturation being a primary cause of reproductive dysfunction. This study examines the effects of HS on porcine oocyte meiotic maturation and evaluates the protective role of L-aspartic acid (L-Asp) supplementation during this process. Here, we report that L-Asp supplementation improves the quality of porcine oocytes under heat stress. More specifically, we found that heat stress resulted in oocyte maturation failure by disturbing the dynamics of meiotic organelles, including the spindle assembly, chromosome structure and mitochondrial function. Moreover, heat stress triggered the overproduction of reactive oxygen species (ROS) and caused DNA damage, resulting in apoptosis in oocytes and halting embryonic development. Importantly, our findings showed that L-Asp supplementation during heat stress alleviated the meiotic defects in porcine oocyte maturation. These findings demonstrate that L-Asp supplementation is a beneficial strategy for improving oocyte quality under HS by facilitating both nuclear and cytoplasmic maturation. This approach holds promise as a practical strategy for mitigating the reproductive challenges posed by global warming in livestock production.

2025-05-31 | GSE297045 | GEO

Melatonin, as a downstream molecule of follicle-stimulating hormone, improves nutrient accumulation and mitochondrial function in mammalian oocytes.

Project description:Background: Melatonin (MLT) supplementation has been shown to improve the quality of oocytes and embryos in vitro through its antioxidant mechanism. However, it is unclear whether endogenous MLT plays a role in oocyte quality control, casting doubt on the rationality of oral MLT in improving oocyte quality or fecundity. Methods:we measured the effects of PMSG on MLT synthesis in follicles, evaluated the effects of MLT on oocyte growth and quality in mice and goat, used RNA-seq to explore the mechanism underlying MLT’s effects on oocyte growth and quality, and generated SNAT-knockout mice to assess the effects of endogenous MLT on oocyte growth and quality. Lastly, we investigated the feasibility of short-term MLT intake to improve the fertility of older mice. Result: we revealed that the follicle-stimulating hormone induces the expression of intra-ovarian SNAT, resulting in increased levels of intra-ovarian MLT in mice. Administering MLT during the gonadotropin-dependent phase improved the oocyte size and quality in both mice and goat by enhancing nutrient accumulation and mitochondrial function. Deficiency of MLT in mice reduced oocyte size and weakened mitochondrial function. Furthermore, our findings demonstrate that short-term MLT intake during the gonadotropin phase improves the litter size of older mice. Conclusion: This study reveals that endogenous MLT is involved in determining oocyte quality as a target molecule of follicle-stimulating hormone, shedding light on its potential utilization in improving oocyte quality or rejuvenating aged mammalian oocytes.

2023-08-12 | GSE240209 | GEO

Rejuvenation of aged oocyte through exposure to young follicular microenvironment

Project description:Reproductive aging is a major cause of fertility decline, attributed to decreased oocyte quantity and competence. Follicular somatic cells play crucial roles in the growth and development of the oocyte by providing nutrients and regulatory factors. Here we investigated how oocyte quality is affected by its somatic cell environment by creating chimeric follicles, whereby an oocyte from one follicle was transplanted into and cultured within another follicle whose native oocyte was removed. Somatic cells within the chimeric follicle re-establish connections with the oocyte and support oocyte growth and maturation in a three-dimensional (3D) culture system. We show that young oocytes transplanted into aged follicles exhibited reduced meiotic maturation and developmental potential, whereas the young follicular environment significantly improved the rates of maturation, blastocyst formation and live birth of aged oocytes. Aged oocytes cultured within young follicles exhibited enhanced interaction with somatic cells, more youth-like transcriptome, remodelled metabolome, improved mitochondrial function, and enhanced fidelity of meiotic chromosome segregation. These findings provide the basis for a future follicular somatic cell-based therapy to treat age-associated female infertility.

2024-07-22 | GSE270016 | GEO

Histone Demethylase-Assisted Somatic Cell Nuclear Transfer Facilitates Derivation of Human Pluripotent Stem Cells

Project description:The extremely low efficiency of human embryonic stem cell (hESC) derivation using somatic cell nuclear transfer (SCNT) limits potential application. Blastocyst formation from human SCNT embryos occurs at a low rate and with only some oocyte donors. We previously showed in mice that reduction of histone H3 lysine 9 trimethylation (H3K9me3) through ectopic expression of the H3K9me3 demethylase Kdm4d greatly improves SCNT embryo development. Here we show that overexpression of a related H3K9me3 demethylase KDM4A improves human SCNT, and that, as in mice, H3K9me3 in the human somatic cell genome is an SCNT reprogramming barrier. Overexpression of KDM4A significantly improves the blastocyst formation rate in human SCNT embryos by facilitating transcriptional reprogramming, allowing derivation of NTESCs from all oocyte donors tested using adult AMD patient somatic nuclei donors. This conserved mechanistic insight has potential applications for improving SCNT in a variety of contexts, including regenerative medicine. Here we perform RNA-seq based transcriptome profiling in human Donor (fibroblast cells), in vitro fertilized embryos at 8-cell stages (IVF_8Cell), somatic cell nuclear transfer embryos at 8-cell stages (SCNT_8Cell), SCNT assisted by KDM4A 8-cell embryos (SCNT_KDM4A_8Cell). Besides, we also perform RNA-seq in Control human ES cells (CTR_hES) and SCNT assisted by KDM4A derived human ES cells (NTK) with duplicates.Â

2016-03-01 | E-GEOD-73362 | biostudies-arrayexpress

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