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Spatial Transcriptomic Atlas Reveals that FOXO3-Mediated Mitochondrial Dynamics Imbalance Drives Premature Ovarian Insufficiency in Mice

ABSTRACT: Premature ovarian insufficiency (POI) is a major cause of female reproductive aging, yet its underlying mechanisms remain poorly understood. Traditional studies have struggled to reveal the spatial and structural aging patterns of POI ovaries. This study constructed a spatial transcriptomic atlas of POI mouse ovaries to define the spatial and molecular features of granulosa-cell senescence during disease progression. Spatial analysis revealed disrupted follicular structure and distinct granulosa-cell subpopulations with blocked differentiation and senescence-associated gene signatures. Integration of related gene sets identified mitochondrial structural and functional impairment as a central feature of granulosa-cell senescence in POI. These changes were accompanied by excessive mitochondrial fission, reduced fusion, loss of mitochondrial membrane potential(MMP), reduced adenosine triphosphate (ATP) production, and increased reactive oxygen species (ROS). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis implicated the FOXO signaling pathway in mitochondrial dysfunction. Consistently, FOXO3 phosphorylation was significantly reduced in POI ovarian tissues. Pharmacological inhibition of this aberrant FOXO3 activation in a triptolide-induced POI model using KGN cells partially restored mitochondrial morphology and function. Suppressing FOXO3 phosphorylation in normal KGN cells was sufficient to induce mitochondrial dysfunction. Together, these findings demonstrate that FOXO3-mediated disruption of mitochondrial dynamics drives granulosa-cell senescence and contributes to ovarian failure in POI. By combining spatial transcriptomics with functional and mechanistic analyses, this study provides a spatially resolved framework for understanding ovarian aging and identifies FOXO3-regulated mitochondrial pathways as promising targets for diagnosis and therapeutic intervention in POI.

ORGANISM(S): Mus musculus

PROVIDER: GSE334364 | GEO | 2026/07/15

REPOSITORIES: GEO

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Project description:Female infertility syndromes are among the most prevalent chronic health disorders in women, but their molecular basis remains unknown because of the complexity of oogenesis and uncertainty regarding the number and identity of ovarian factors controlling the assembly, preservation, and maturation of ovarian follicles. To systematically discover such ovarian fertility factors en masse, we employed a mouse model (Foxo3), where follicles are assembled normally but are then synchronously activated. Gene expression profiling of mutant and normal ovaries led to the identification a surprisingly large set of ovarian factors. The set included the vast majority of known ovarian factors, many of which when mutated produce female sterility phenotypes, but most were novel. Subsequent analyses revealed novel classes of ovarian factors and significant overrpresentation on the X chromosome, among other insights into the general properties of oogenesis genes and their patterns of expression. Experiment Overall Design: Total ovarian RNA from +/+ and -/- ovaries at PND1, 3, 7, and 14 (n=3 replicates per timepoint and genotype, a total of 24 microarrays) was subjected to linear RNA amplification and hybridized to Affymetrix 430 2.0 mouse whole-genome microarrays, which interrogate >39K transcripts including the vast majority of protein-coding genes. We also profiled 14 somatic tissues. Additionally, to provide more refined views of gene expression, we profiled adult ovaries, adult testis, KitlSl/KitlSl-d testis (devoid of germ cells except for rare spermatogonia) (Shinohara et al., 2000), ES cells, laser-capture microdissected (LCM) primary oocytes, LCM somatic cells (granulosa cells + surrounding stroma), superovulated unfertilized eggs, cumulus granulosa cells, and E11 Foxo3 +/+ and -/- embryos. Each array data set was independently normalized by global median scaling, and the signal strengths were averaged for those samples for which replicates were available (PND1-14).

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Spatial Transcriptomic Atlas Reveals that FOXO3-Mediated Mitochondrial Dynamics Imbalance Drives Premature Ovarian Insufficiency in Mice

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