Obesity May Harm Sperm Motility Through a STAT3/MTND4 Mitochondrial Pathway in Mice

Obesity has long been linked to impaired male fertility, but the molecular chain of events connecting excess body weight to damaged sperm function has remained only partly mapped. A new mouse and cell-culture study, published in Reproductive Sciences, points to a specific mitochondrial signaling axis — the transcription factor STAT3 acting on the mitochondrial gene MTND4 — as a mediator of obesity-related seminal vesicle injury and reduced sperm motility.

The research team established high-fat diet (HFD) models both in living mice and in vitro. In the animal model, HFD feeding produced the expected obesity phenotype: mice gained body weight, showed decreased serum testosterone, and had elevated levels of total cholesterol and triglycerides. These metabolic shifts were accompanied by structural damage in the seminal vesicles, including disorganized tissue architecture and epithelial exfoliation, along with impaired secretory function.

Sperm parameters also deteriorated. Using a computer-aided sperm analysis system, the researchers documented marked reductions in sperm motility, progressive motility, and sperm concentration in the HFD animals. Together, these observations replicate the pattern of reproductive dysfunction previously associated with obesity and set the stage for probing the underlying mechanism.

A central molecular finding concerned MTND4, or mitochondrial NADH dehydrogenase subunit 4, a protein that plays a pivotal role in sustaining the mitochondrial electron transport chain and cellular energy metabolism. In mice fed the high-fat diet, MTND4 expression was markedly upregulated in the seminal vesicles, suggesting that this mitochondrial component responds to the obese metabolic state.

To test what MTND4 overexpression does, the team overexpressed the gene in cell models. The result was a cascade of mitochondrial and oxidative damage: accumulation of reactive oxygen species (ROS), decreased mitochondrial membrane potential as measured by JC-1 staining, and exacerbated oxidative stress assessed through superoxide dismutase and malondialdehyde assays. Functionally, these changes translated into reduced motility and enhanced apoptosis of seminal vesicle cells.

The researchers then looked upstream to find what drives MTND4 upregulation. Using the JASPAR database to forecast candidate transcription factors, they identified STAT3 as a likely regulator. Two independent lines of verification followed: chromatin immunoprecipitation and dual-luciferase reporter assays both confirmed that STAT3 transcriptionally activates MTND4, establishing a direct regulatory relationship rather than a mere correlation in expression patterns.

To place the whole pathway in context, the team constructed a co-transfected HFD cell model combining STAT3 knockdown with MTND4 overexpression. The experiments indicated that HFD reduces seminal vesicle cell viability by upregulating STAT3, which in turn activates MTND4 transcription, driving ROS production and mitochondrial dysfunction. In the authors’ proposed model, this STAT3/MTND4 axis ultimately mediates obesity-related seminal vesicle injury and sperm dysfunction.

The study’s authors suggest that the STAT3/MTND4 axis may be a novel target for regulating male reproductive health. Important caveats apply: the findings derive from mouse and cell models of high-fat diet exposure rather than human clinical data, and the abstract describes planned assays and observed associations in these experimental systems. Whether the same pathway operates in men with obesity, and whether manipulating STAT3 or MTND4 could yield therapeutic benefit, would require further investigation. Nevertheless, by tracing a specific transcriptional route from metabolic stress to mitochondrial dysfunction in the male reproductive tract, the work adds a defined molecular node to the growing map of how obesity may undermine sperm function.

Subject of Research: The role of the STAT3/MTND4 mitochondrial pathway in obesity-related seminal vesicle injury and impaired sperm motility in mouse and cell models.

Article Title: STAT3/MTND4 Mediates Obesity-Related Seminal Vesicle Injury and Impaired Sperm Motility Via Reactive Oxygen Species /Mitochondrial Dysfunction

Article References: Shi, H., Han, G., Zheng, B., Li, J., Xu, J., Rong, C., & Meng, K. (2026). STAT3/MTND4 Mediates Obesity-Related Seminal Vesicle Injury and Impaired Sperm Motility Via Reactive Oxygen Species /Mitochondrial Dysfunction. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02241-1

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02241-1

Keywords: obesity, male fertility, sperm motility, STAT3, MTND4, mitochondrial dysfunction, reactive oxygen species, seminal vesicle, high-fat diet, oxidative stress, reproductive biology, testosterone