Circulating cell-free mitochondrial DNA levels and glucocorticoid receptor sensitivity in combat-related PTSD

Abstract Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a biomarker of cellular injury or cellular stress and is a potential novel biomarker of psychological stress and of various brain, somatic, and psychiatric disorders. No studies have yet analyzed ccf-mtDNA levels in post-traumatic stress disorder (PTSD), despite evidence of mitochondrial dysfunction in this condition. In the current study, we compared plasma ccf-mtDNA levels in combat trauma-exposed male veterans with PTSD (n = 111) with those who did not develop PTSD (n = 121) and also investigated the relationship between glucocorticoid signaling and ccf-mtDNA levels. In unadjusted analyses, ccf-mtDNA levels did not significantly differ between PTSD and non-PTSD groups (t = 1.312, p = 0.191). However, after controlling for the potential confounding variables age, HbA1c, and antidepressant use, the PTSD group had lower ccf-mtDNA levels than did the non-PTSD group (F(1, 221) = 5.509; p = 0.020). We also performed a sensitivity analysis excluding diabetics and antidepressant users and found that the PTSD group still had significantly lower ccf-mtDNA levels (t = 2.577, df = 177, p = 0.011). Across the entire sample, ccf-mtDNA levels were negatively correlated with post-dexamethasone ACTH decline (r=-0.171, p = 0.020) and cortisol decline (r=-0.149, p = 0.034) (viz., greater ACTH and cortisol suppression was associated with lower ccf-mtDNA levels) both with and without controlling for age, antidepressant status and HbA1c. Ccf-mtDNA levels were also significantly positively associated with IC 50 − DEX , a measure of lymphocyte glucocorticoid receptor (GR) sensitivity, after controlling for age, antidepressant status, and HbA1c (β = 0.135, p = 0.043), suggesting that increased lymphocyte GR sensitivity is associated with lower ccf-mtDNA levels. Although no overall group differences were found in unadjusted analyses, exclusion of diabetics and antidepressants, which may affect ccf-mtDNA levels, revealed decreased ccf-mtDNA levels in PTSD. In both adjusted and unadjusted analyses, low ccf-mtDNA levels were associated with relatively increased GR sensitivity, often reported in PTSD, suggesting a link between mitochondrial and glucocorticoid signaling abnormalities in PTSD.