Work

Dysregulation of alternative splicing patterns in the ovaries of reproductively aged mice

Year: 2026

Type: article

Abstract: Female reproductive aging is characterized by progressive deterioration of ovarian function, yet the molecular mechanisms driving these changes remain incompletely understood. Here, we used long-read direct RNA-sequencing to map transcript isoform changes in mouse ovaries across reproductive age. Comparing young and aged mice after controlled gonadotropin stimulation, we identified widespread alternative splicing changes, including shifts in exon usage, splice site selection, and transcript boundaries. Aged ovaries exhibited increased isoform diversity, favoring distal start and end sites, and a significant rise in exon skipping and intron retention events. Many of these age-biased splicing events altered open reading frames, introduced premature stop codons, or disrupted conserved protein domains. Notably, several mitochondrial genes involved in the respiratory chain were affected. We highlight Ndufs4, a mitochondrial Complex I subunit, as a case in which aging promotes the alternative splicing of a short isoform lacking the canonical protein family (Pfam) domain. Structural modeling suggests this splice variant could impair Complex I function, resulting in increased reactive oxygen species production. Our data suggest a mechanistic link between splicing and mitochondrial dysfunction in the aging ovary. These findings support the model of the splicing-energy-aging axis in ovarian physiology, wherein declining mitochondrial function and adaptive or maladaptive splicing changes are intertwined. Our study reveals that alternative splicing is not merely a byproduct of aging but a dynamic, transcriptome-wide regulatory layer that may influence ovarian longevity. These insights open new avenues for investigating post-transcriptional mechanisms in reproductive aging and underscore the need to consider isoform-level regulation in models of ovarian decline.

Source: Reproduction

DOI: 10.1093/reprod/xaag019

Authors: Adnan T Alsamaraee, Vanessa L Correll, Julius O Nyalwidhe, Pavla Brachova, Nehemiah S Alvarez

Institutions: Eastern Virginia Medical School, Old Dominion University

Language: English

Topic: RNA Research and Splicing

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Funders: Old Dominion University, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development

Awards: A-to-I RNA modifications in mouse oocytes, Designing effective RNA therapies for oocyte maturation, Deciphering The Role of RNA Modifications In Maternal Mrna Clearance