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bioRxiv · 10.1101/2025.07.30.667787

Mitochondrial Response to Psychological Stress and Its Medial Prefrontal Biomarker Correlates

Ankeeta, A.·Tripathi, A.·Ma, Y.·Pillai, B.·Chiappelli, J. J.·Jernberg, J. N.·Kunitoki, K.·Adhikari, B. M.·Gao, S.·Du, X.·Kabui, L.·Solano, F. P.·Akindona, O.·Ye, Z.·Chen, S.·Milad, M.·Kochunov, P.·Pillai, A. R.·Hong, E. L.
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Abstract

BackgroundStress response obligates increased mitochondrial activities to meet stress-induced high energy requirement. This stress-mitochondrial response process involves glucocorticoid but also multiple alternative pathways that are top-down regulated by the medial prefrontal cortex (mPFC). These pathways are important for many neuropsychiatric conditions that are sensitive to stress. However, the field lacks a reliable, clinically accessible stress-mitochondrial response paradigm to study the process in humans. MethodWe used an established psychological stress challenge combined with assaying salivary cell-free mitochondrial DNA (cf-mtDNA), thought to reflect heightened mitochondrial changes or disruptions, in 35 healthy individuals (21 males). We also explored if these stress-induced cf-mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS), as well as high-resolution brain imaging based cortical thickness focusing on the mPFC. ResultsWe found that salivary cf-mtDNA was significant elevated immediately after the stress challenge (p=2.0x10-7) and gradually declined after. Exploratory causal analysis showed that this cf-mtDNA response was not primarily driven by cortisol response. Instead, individuals with higher baseline dACC lactate+ levels, thought to in part reflect mitochondrial dysfunctions, was significantly associated with the cf-mtDNA response (r=0.80, p<0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r=-0.52, p=0.01). Age had a U-shape effect such that cf-mtDNA response trended lower in earlier adulthood but higher in older people, explaining 33.8% of the ct-mtDNA response variance (p=0.003). ConclusionThis stress challenge-salivary cf-mtDNA assay paradigm may offer a new, non-invasive approach to evaluate the stress-mitochondrial pathway functioning in aging, psychopharmacology, and neuropsychiatric conditions where psychological stress plays a role.

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Ankeeta, A., Tripathi, A., Ma, Y., Pillai, B., Chiappelli, J. J., Jernberg, J. N., Kunitoki, K., Adhikari, B. M., Gao, S., Du, X., Kabui, L., Solano, F. P., Akindona, O., Ye, Z., Chen, S., Milad, M., Kochunov, P., Pillai, A. R., Hong, E. L.. 2025-08-01. Mitochondrial Response to Psychological Stress and Its Medial Prefrontal Biomarker Correlates. https://doi.org/10.1101/2025.07.30.667787

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