Sex-specific effects of chronic unpredictable stress on mitochondrial function in the HPA axis in mice

Crockett, A. M.; Frambes, N. I.; Mullaly, A.; Churillo, A. M.; Dos Passos, R. R.; Folk, C.; Freeburg, L.; Cavalli, E.; Gardiner, J.; Harrington, E. N.; Philbeck, T. L.; Wilczynski, S.; Priviero, F.; Spinale, F. G.; Webb, R. C.; Wood, S. K.; Ryan, M. J.; Hollis, F.

doi:10.1101/2025.07.28.667247

bioRxiv · 10.1101/2025.07.28.667247

Sex-specific effects of chronic unpredictable stress on mitochondrial function in the HPA axis in mice

Crockett, A. M.·Frambes, N. I.·Mullaly, A.·Churillo, A. M.·Dos Passos, R. R.·Folk, C.·Freeburg, L.·Cavalli, E.·Gardiner, J.·Harrington, E. N.·Philbeck, T. L.·Wilczynski, S.·Priviero, F.·Spinale, F. G.·Webb, R. C.·Wood, S. K.·Ryan, M. J.·Hollis, F.

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Abstract

Stress, whether real or perceived, activates physiological and behavioral responses via the hypothalamic- pituitary-adrenal (HPA) axis and sympathetic nervous system activation. Under chronic stress, however, these adaptive responses become dysfunctional leading to pathological changes in behavior and health. Mitochondria are dynamic organelles essential for cellular energy production and for initiating glucocorticoid synthesis and release from adrenal glands during stress. Thus, mitochondria may represent a first line of response to environmental challenges. However, the effects of chronic stress on mitochondrial function within the HPA axis, particularly regarding sex differences, are unexplored. We exposed adult male and female C57BL6/J mice to four weeks of chronic unpredictable stress and examined behavioral and mitochondrial responses in the hypothalamus and adrenal glands - two key HPA axis regions. As previous reports indicated sex differences in stress responsivity, we hypothesized that chronic stress would differentially impact mitochondrial respiration within HPA axis regions in a sex-specific manner. Chronic stress increased avoidance behavior in males and passive coping behavior in females, indicating sex-specific behavioral responses. In females, stress significantly decreased mitochondrial respiration in both the hypothalamus and adrenal glands, while males were not significantly affected. In males, stress increased adrenal expression of mitochondrial complex II protein, which may have served a compensatory role to preserve mitochondrial function. Mitochondrial respiration significantly correlated with behavioral measures in stressed animals, highlighting a relationship between metabolism and stress-induced impairments. These findings reveal sex-specific metabolic adaptations to chronic stress and suggest that females may be more vulnerable to stress-induced mitochondrial dysfunction within the HPA axis. Clinical PerspectivesO_LIChronic stress is widely prevalent, associated with neuropsychiatric disease that affect women at a rate twice as high as men, and mediated by mitochondria, yet sex differences in the effects of chronic stress on mitochondrial function have not been characterized. C_LIO_LIDespite similar behavioral outcomes, chronic unpredictable stress exposure significantly decreases mitochondrial respiration only in the hypothalamus and adrenal glands from females, in association with stress-induced behavioral alterations. C_LIO_LIFemales may have increased vulnerability to metabolic effects of chronic stress and therapies targeting mitochondrial function may be more efficacious in preventing behavioral impacts of stress in females. C_LI

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Crockett, A. M., Frambes, N. I., Mullaly, A., Churillo, A. M., Dos Passos, R. R., Folk, C., Freeburg, L., Cavalli, E., Gardiner, J., Harrington, E. N., Philbeck, T. L., Wilczynski, S., Priviero, F., Spinale, F. G., Webb, R. C., Wood, S. K., Ryan, M. J., Hollis, F.. 2025-07-30. Sex-specific effects of chronic unpredictable stress on mitochondrial function in the HPA axis in mice. https://doi.org/10.1101/2025.07.28.667247

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