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<p>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, <i>N</i> = 16), as well as high-resolution brain imaging based cortical thickness focusing on the mPFC (<i>N</i> = 30). We found that salivary cf-mtDNA was significantly elevated immediately after the psychological stress challenge (<i>p</i> = 2.0 × 10<sup>−7</sup>) 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, <i>p</i> &lt; 0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r = −0.52, <i>p</i> = 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 (<i>p</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • A. Ankeeta,
  • Ashutosh Tripathi,
  • Yizhou Ma,
  • Bindu Pillai,
  • Joshua J. Chiappelli,
  • Jennifer N. Jernberg,
  • Alia Warner,
  • Keiko Kunitoki,
  • Bhim M. Adhikari,
  • Si Gao,
  • Xiaoming Du,
  • Loise Kabui,
  • Francisco Pallares Solano,
  • Oluwabunmi Akindona,
  • Zhenyao Ye,
  • Shuo Chen,
  • Mohammad Milad,
  • Peter Kochunov,
  • Anilkumar Pillai,
  • L. Elliot Hong

摘要

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.