How stress reduces sperm motility by altering mitochondria

By Dr. Sushama R. Chaphalkar, PhD.Reviewed by Benedette Cuffari, M.Sc.Sep 16 2024

New study reveals how stress boosts sperm motility through mitochondrial changes and epigenetic shifts.

Study: Stress increases sperm respiration and motility in mice and men. Image Credit: Rost9 / Shutterstock.com

In a recent study published in Nature Communications, researchers investigate the effects of perceived stress on sperm motility and maturation.

Stress was found to increase sperm motility in humans after two to three months. In mice, stress induces differential gene regulation and alters extracellular vesicle (EV) composition which subsequently leads to altered sperm mitochondrial activity and motility.

Stress and fertility

Stress influences long-term reproductive fitness; however, the underlying cellular and molecular mechanisms responsible for the impact of stress on fertility remain unclear. Evidence suggests that prolonged stress induces allostasis, a process where stress-induced changes in cellular function persist after the stress ends.

Epididymal epithelial cells (EECs) in males secrete factors and cargo-carrying EVs, which are critical for sperm maturation. Previous research indicates that stress-induced changes in EEC-secreted EVs affect sperm composition and fertility.

The glucocorticoid receptor (GR), which is central to stress responses, influences mitochondrial and transcriptional processes. In the present study, researchers examine how stress alters sperm function through metabolic and mitochondrial pathways, particularly involving GRs. The researchers also investigate the effects of prior perceived stress on sperm motility in men.

About the study

A total of 34 healthy males between 18 and 35 years of age were recruited from the University of Colorado and Denver Metropolitan area using social media and flyers. Study participants were screened for medical history and excluded based on specific criteria, including psychotropic medication use, substance abuse, and sperm abnormalities.

All participants completed assessments, including the perceived stress scale (PSS), and provided semen samples after a two-day abstinence period. Semen samples were processed according to recommendations from the World Health Organization (WHO) and analyzed using a computer-assisted sperm analyzer. Mixed-effects modeling was used to assess the association between sperm velocity and prior perceived stress.

For in vitro experiments, immortalized mouse distal caput epididymal epithelial (DC2) cells were cultured and treated with corticosterone. Sperm and EVs were isolated from male mice and co-incubated.

Cleavage Under Targets and Release Using Nuclease (CUT&RUN) and ribonucleic acid (RNA) isolation were performed to study gene expression and chromatin modifications. Respirometry was conducted to assess oxygen consumption rates in DC2 cells and sperm.

Complex I enzyme activity was measured to evaluate mitochondrial function. Western immunoblotting was used for protein analysis, whereas transmission electron microscopy provided visualization of mitochondrial structures.

Blinding and randomization were used in both human cohort and in vitro animal studies to reduce bias. Various bioinformatics tools and statistical methods were used for data analysis.

Study findings

Sperm volume, concentration, and motility did not change significantly in humans. PSS at three months prior to sperm collection was positively associated with average path velocity (VAP), curvilinear velocity (VCL), and straight line velocity (VSL). Higher PSS at this time point correlated with increased sperm motility metrics, whereas PSS at the time of collection and previous two months were not significantly different.

In vitro, over half of the binding sites of H3K27me3, a stress responsive transcriptional repressor, were located near gene promoters, with 7,282 regions exhibiting changes in H3K27me3. Binding sites were linked to genes involved in mitochondrial organization and metabolism, thus indicating that prior stress may impact sperm maturation through persistent changes in gene regulation.

A total of 11 gene modules and 272 differentially expressed genes were identified, with the mitochondrial function-related module strongly correlating with prior corticosterone treatment. Corticosterone treatment reduced basal mitochondrial respiration and adenosine triphosphate (ATP) production in EECs while increasing mitochondrial orthodox ultrastructure.

Changes in GR localization were observed, along with reduced nuclear GR, increased mitochondrial GR, and altered sperm respiration. Substrate injection indicated reduced respiration for complex I substrates in post-corticosterone EECs.

EVs from corticosterone-treated EECs were smaller and increased sperm mitochondrial respiration and ATP production rates. Exposure to EVs from corticosterone-treated EECs enhanced sperm motility parameters, including curve velocity, VAP, and VSL, without affecting overall motility percentage.

Conclusions

The study findings reveal a time-dependent association between prior perceived stress and crucial sperm functions. EVs were also identified as important intercellular communicators with potential therapeutic applications to enhance sperm function. Several other important molecular processes were linked to allostasis, particularly mitochondrial and epigenetic changes triggered by stress.

Taken together, these observations suggest that stress management could be a crucial component in improving reproductive outcomes in men, thus emphasizing the need for a holistic approach in fertility assessments and treatments.