Psychological stress induced mitochondrial response in humans and its medial prefrontal biomarker correlates

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Psychological stress induced a significant immediate increase in salivary cell-free mitochondrial DNA, peaking post-challenge and declining thereafter (p = 2.0 × 10-7).
cf-mtDNA response was only nominally related to cortisol but strongly correlated with baseline mPFC/dACC lactate+ levels, indicating mitochondrial dysfunction (r = 0.80, p < 0.001).
Higher cf-mtDNA response associated with thinner dorsomedial prefrontal cortex and exhibited a U-shaped age effect, explaining 33.8% of variance (p = 0.003).

Transl Psychiatry. 2026 Jul 20. doi: 10.1038/s41398-026-04246-5. Online ahead of print.

ABSTRACT

Stress 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. We 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, N = 16), as well as high-resolution brain imaging based cortical thickness focusing on the mPFC (N = 30). We found that salivary cf-mtDNA was significantly elevated immediately after the psychological stress challenge (p = 2.0 × 10^-7) and gradually declined after. Exploratory analyses indicated that the cf-mtDNA response was only nominally associated with the cortisol response and was not substantially driven by changes in cortisol. Instead, we found that higher baseline mPFC/dACC lactate+ levels, which may partly reflect mitochondrial dysfunction were 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 = 0.003). 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). This 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.

PMID:42477317 | DOI:10.1038/s41398-026-04246-5

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