Circulating cell-free mitochondrial DNA, but not leukocyte mitochondrial DNA copy number, is elevated in major depressive disorder

Lars Ohlsson,Daniel Lindqvist,Martin Picard,Johan Fernström,Elissa S Epel,Francesco S Bersani,Christina M Hough,Jue Lin,Åsa Westrin,Synthia H Mellon,Victor I Reus,Owen M Wolkowitz

doi:10.1038/s41386-017-0001-9

Abstract

Major depressive disorder (MDD) has been linked to mitochondrial defects, which could manifest in mitochondrial DNA (mtDNA) polymorphisms or mutations. Additionally, copy number of mtDNA (mtDNA-cn) can be quantified in peripheral blood mononuclear cells (PBMC)s, indirectly reflecting cellular energetics, or in the circulating cell-free mtDNA (ccf-mtDNA) levels, which may reflect a fraction of the mitochondrial genome released during cellular stress. Few studies have examined ccf-mtDNA in MDD, and no studies have tested its relationship with intracellular mtDNA-cn or with antidepressant treatment response. Here, mtDNA levels were quantified in parallel from: (i) PBMCs and (ii) cell-free plasma of 50 unmedicated MDD subjects and 55 controls, in parallel with PBMC telomere length (TL) and antioxidant enzyme glutathione peroxidase (GpX) activity. MtDNA measures were repeated in 19 MDD subjects after 8 weeks of open-label SSRI treatment. In analyses adjusted for age, sex, BMI, and smoking, MDD subjects had significantly elevated levels of ccf-mtDNA (F = 20.6, p = 0.00002). PBMC mtDNA-cn did not differ between groups (p > 0.4). In preliminary analyses, we found that changes in ccf-mtDNA with SSRI treatment differed between SSRI responders and non-responders (F = 6.47, p = 0.02), with the non-responders showing an increase in ccf-mtDNA and responders not changing. Baseline ccf-mtDNA was positively correlated with GpX (r = 0.32, p = 0.001), and PBMC mtDNA correlated positively with PBMC TL (r = 0.38, p = 0.0001). These data suggest that plasma ccf-mtDNA and PBMC mtDNA-cn reflect different cellular processes and that the former may be more reflective of certain aspects of MDD pathophysiology and of the response to SSRI antidepressants.

Highlights

Mitochondrial dysfunction may be involved in the pathophysiology of Major depressive disorder (MDD) [1,2,3,4,5]
Our results show that ccf-mitochondrial DNA (mtDNA) is significantly higher in unmedicated MDD subjects compared to healthy controls, but that cellular (PBMC) mtDNA-cn does not significantly differ between groups
peripheral blood mononuclear cells (PBMC) mtDNA-cn likely reflects intracellular mtDNA content and bioenergetics [6], independent of apoptosis; ccf-mtDNA is likely released from cells during cellular stress [19, 40] and does not contribute to cell energetics

Summary

Introduction

Cells contain multiple mitochondria and, in turn, each mitochondrion contains multiple copies of its own genome, the mitochondrial DNA (mtDNA), which encodes 37 genes essential to energy production [6]. As a result of these mechanisms, mitochondrial impairments may be associated with, and/or lead to, psychiatric manifestations such as mood and anxiety disorders, conditions that have been associated with cellular senescence and oxidative stress. MtDNA may be released at low levels into the circulation from mitochondria under cellular stress, resulting in circulating cell-free mtDNA (ccf-mtDNA) detectable in plasma [14, 15]. Ccf-mtDNA has only very recently been assessed in psychiatric patients after suicide attempt [16], and in MDD subjects [17]

Methods

Results

Conclusion