# Transduction of Psychological Stress into Systematic Inflammation by Mitochondrial DNA Signaling

> **NIH NIH R01** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2022 · $681,923

## Abstract

PROJECT SUMMARY
Systemic inflammation is believed to contribute to the damaging health effects of psychological stress. In the
laboratory setting, a single acute bout of socioevaluative stress leads to a delayed elevation of pro-
inflammatory cytokines in healthy adults. However, the biological mechanisms by which psychological stress is
transduced into inflammation is not well understood. A cellular component known to contribute to stress
signaling is the mitochondrion – a bacteria-derived organelle with its own genome, the mitochondrial DNA
(mtDNA). Recent evidence has demonstrated that various stressors induce the release of mitochondria-
derived signaling molecules, or mitokines. Mitokines travel systemically and modulate central physiological
processes, including immune cell function and the production of pro-inflammatory cytokines. One key mitokine
is circulating cell-free mtDNA (ccf-mtDNA), which arises from mitochondrial extrusion of mtDNA, is recognized
by the toll-like receptor 9 (TLR-9), and leads to pro-inflammatory cytokine production in animal and human
cells. Our preliminary data showed that ccf-mtDNA release, but not ccf-nuclear DNA, is acutely induced
following a brief experimental psychological stress in humans. Thus, we suggest that ccf-mtDNA may be a
missing link in the stress-inflammation cascade. In parallel, imaging and molecular studies on cellular systems
suggests that ccf-mtDNA may be rapidly induced by primary neuroendocrine stress mediators, including
glucocorticoids. This proposal will use an experimental socio-evaluative stress task, counterbalanced with a
control no-stress visit for each participant, to map the kinetics of reactivity and recovery in ccf-mtDNA and
other stress mediators in healthy women and men. Aim 1 will establish: i) the magnitude and kinetics of ccf-
mtDNA release; ii) the specificity of this response compared to nuclear DNA; iii) examine potential sex
differences in this process; and iv) statistically test ccf-mtDNA as a mediator of the subsequent increase in pro-
inflammatory cytokines. In Aim 2, cellular and molecular studies will determine: i) whether primary
glucocorticoid and catecholamine stress hormones are sufficient to trigger ccf-mtDNA release in primary
human cultured cells and isolated leukocytes; ii) image in living cells mtDNA release in response to stress
signaling; and iii) document physical changes in mtDNA structure that contribute to ccf-mtDNA release. Finally,
Aim 3 will establish: i) the capacity of ccf-mtDNA from peak ccf-mtDNA serum to activate cytokine production in
target cells; ii) the structural form and accessibility of ccf-mtDNA in human serum (from Aim 1); and iii) the
dependency on TLR-9 for immune activation. Overall, these studies will contribute mechanistic evidence for a
novel mitochondria-mediated mechanisms for transducing stress into inflammation in humans. Outcomes from
this work will identify new potential targets to improve stress-related mental health an...

## Key facts

- **NIH application ID:** 10359137
- **Project number:** 5R01MH119336-04
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Brett A Kaufman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $681,923
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359137

## Citation

> US National Institutes of Health, RePORTER application 10359137, Transduction of Psychological Stress into Systematic Inflammation by Mitochondrial DNA Signaling (5R01MH119336-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10359137. Licensed CC0.

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