Plasma circulating cell-free mitochondrial DNA in depressive disorders

Abstract

Background Plasma circulating cell-free mitochondrial DNA (ccf-mtDNA) is an immunogenic molecule and a novel biomarker of psychiatric disorders. Some previous studies reported increased levels of ccf-mtDNA in unmedicated depression and recent suicide attempters, while other studies found unchanged or decreased ccf-mtDNA levels in depression. Inconsistent findings across studies may be explained by small sample sizes and between-study variations in somatic and psychiatric co-morbidity or medication status. Methods We measured plasma ccf-mtDNA in a cohort of 281 patients with depressive disorders and 49 healthy controls. Ninety-three percent of all patients were treated with one or several psychotropic medications. Thirty-six percent had a personality disorder, 13% bipolar disorder. All analyses involving ccf-mtDNA were a priori adjusted for age and sex. Results Mean levels in ccf-mtDNA were significantly different between patients with a current depressive episode (n = 236), remitted depressive episode (n = 45) and healthy controls (n = 49) (f = 8.3, p<0.001). Post-hoc tests revealed that both patients with current (p<0.001) and remitted (p = 0.002) depression had lower ccf-mtDNA compared to controls. Within the depressed group there was a positive correlation between ccf-mtDNA and “inflammatory depression symptoms” (r = 0.15, p = 0.02). We also found that treatment with mood stabilizers lamotrigine, valproic acid or lithium was associated with lower ccf-mtDNA (f = 8.1, p = 0.005). Discussion Decreased plasma ccf-mtDNA in difficult-to-treat depression may be partly explained by concurrent psychotropic medications and co-morbidity. Our findings suggest that ccf-mtDNA may be differentially regulated in different subtypes of depression, and this hypothesis should be pursued in future studies.

Circulating Cell-Free DNA Levels in Psychiatric Diseases: A Systematic Review and Meta-Analysis

“…For the same reason, one report on cf-gDNA was excluded from the DDs group [ 36 ], as the remaining studies analyzed cf-mtDNA. Ultimately, the following numbers of reports were included in the meta-analysis: schizophrenia, 8 [ 24 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]; BD, 4 [ 25 , 35 , 43 , 44 ]; DDs, 5 [ 35 , 45 , 46 , 47 , 48 ]. The total number of individual studies included in the meta-analysis was sixteen because some reports considered several diseases simultaneously.…”

“…Among the eight reports in the schizophrenia group, one report examined total the cfDNA and cf-gDNA in first-episode psychosis (FEP) patients [ 42 ]. In the DDs group, three reports included patients diagnosed with major depressive disorder (MDD) [ 35 , 47 , 48 ], one report included individuals with current depression [ 46 ], and one study included suicide attempters [ 45 ]. We accounted for this heterogeneity in the meta-analysis (see below).…”

“…The cfDNA concentration was presented in various units of measurement. Eight studies reported cfDNA concentrations as ng/mL (or pg/mL) [ 24 , 36 , 37 , 39 , 40 , 41 , 42 , 48 ], five as copies/µL [ 35 , 43 , 44 , 46 , 47 ], two as GE/mL (or U/mL) [ 25 , 45 ], and one as nM [ 38 ]. All selected studies were published between 2015 and 2022.…”

“…However, the funnel plot showed signs of publication bias, as many of the studies were outside the confidence intervals ( Figure 3 d). We further excluded two reports with non-specific depressive symptoms [ 45 , 46 ] and analyzed only reports with MDD to reduce the sample heterogeneity. However, the results have not changed (SMD = −0.16, 95% CI = [−0.43 to 0.11]; test for overall effect: Z = 1.18, p = 0.24).…”

Common methods in mitochondrial research (Review)

“…Moreover, after the mitochondria are separated from cells or tissues, the dNA in the remaining material is extracted (kits can be used) and the dNA of the sample can be sequenced. qPcR or chromatin immunoprecipitation (chIP) experimental methods can be used to detect the level of ccF-mtdNA, among which chIP is often used to verify the binding of mtdNA to downstream signaling pathways, such as TLR9 inflammatory pathway or cGAS signaling pathway (335,(363)(364)(365)(366)(367)(368)(369)(370)(371). As a dNA sensor in the cytoplasm, cGAS can recognize ccF-mtdNA and then catalyze the formation of the second messenger cGAMP (2'3'-cGAMP) to activate the interferon-stimulated gene-dependent signaling pathway.…”