Sex-specific effects of antioxidant treatment in chronic stress induced behavioral and mitochondrial dysfunction in mice

Background: Globally, 1 in 4 adults report that stress impedes their daily functioning. Chronic stress exposure leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), resulting in behavioral and physiological disruptions, especially in females, as they are at increased risk of developing psychiatric diseases. We previously showed that chronic unpredictable stress (CUS) imposed sex- and region-specific deficiencies on mitochondrial function linked to behavioral pathology and elevated blood pressure. However, whether mitochondria have a functional role in modulating stress pathology is unclear. Dysfunctional mitochondria release immunogenic molecules, such as reactive oxygen species (ROS), which can accumulate, further exacerbating dysfunction. Mitochondrial-targeted antioxidants like mitoquinol (MitoQ) can scavenge ROS to alleviate accumulation. Here, we investigated whether co-treatment with MitoQ could prevent the pathological effects of CUS. Hypothesis: CUS will induce behavioral pathology and mitochondrial dysfunction within key HPA axis regions, which will be prevented with MitoQ co-treatment. Methods: Adult male and female C57Bl6/J mice were assigned to either non-stress or CUS and vehicle (water) or MitoQ (0.5mM in drinking water) treatment groups. Animals were habituated to MitoQ for one week and then exposed to 28 days of CUS or light handling (non-CUS). Food and water intake were monitored alongside body weight weekly. During the last week of stress, avoidance behavior was evaluated using the Elevated Plus Maze (EPM) and Open Field Test (OFT). Systolic Blood Pressure (SBP) was measured via tail cuff. At euthanasia, the hypothalamus and adrenal glands were collected to assess mitochondrial function via high-resolution respirometry. Results: CUS decreased body weight gain in males (p=.04) with no effect of MitoQ treatment. In females, CUS increased avoidance behavior in the EPM (p=.005), which was partially prevented in stressed females by MitoQ (p=.34 vs non-CUS). MitoQ additionally reduced avoidance behavior in non-stressed females (p=.03) in the OFT. Sex, CUS, and MitoQ marginally interacted to prevent CUS-induced elevated SBP in males (p=.06). MitoQ overall enhanced mitochondrial respiration in the hypothalamus (p=0.04) but had no effect on adrenal gland respiration. Conclusions: Here we show that MitoQ treatment exhibits sex-specific effects on behavioral and physiological responses to CUS. These results support MitoQ as a potential therapeutic intervention for stress-induced HPA axis dysregulation and show that mitochondria have a functional role in stress-induced pathologies. This work was supported by funding from MitoQ (FH), NIH grants 1R01HL179186 (FH), U54HL169191 (FH), R01DK132948 (RCW); VA merit awards BX006218 (FH), and University of South Carolina Office of the Vice President for Research (FH, RCW). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.