Gene Expression Profile in Major Depressive Disorder Shows Reduced Mitochondrial Biogenesis

Mitochondria are relevant organelles present in eukaryotic cells and whose principal function is ATP production by the oxidative phosphorylation (OXPHOS) pathway. They also play crucial roles in many other metabolic, regulatory, and developmental processes 1. Mitochondrial biogenesis is activated by modulation of the ATP/ADP ratio, activation of an AMP-activated protein kinase (AMPK), and subconsequent expression of PGC-1α and NRF1 transcriptional factors 1. The involvement of mitochondria in a variety of pathological mechanisms has been partially ascribed to their central role in reactive oxygen species (ROS) production and to the damaging effect mediated by ROS themselves on the same organelles 1. PGC-1α has also been involved in the cellular response against oxidative stress damage through increased expression levels of antioxidant enzymes such as MnSOD and catalase 1. Major depressive disorder (MDD) is an important psychiatric disease characterized by a significant mood change accompanied by other symptoms such as anhedonia, low self-esteem, with disrupted sleeping, cognition, and eating. It is estimated to be the second major illness measured by social and economic burden by 2020 2. MDD affects up to 10% of the general population worldwide; however, its pathogenic mechanism remains elusive 2. Consequently, the pathophysiology of cellular and molecular levels of MDD is being characterized. According to this, several hypotheses and pilot studies suggest important role of inflammation, oxidative stress, and mitochondrial dysfunction(definition) in MDD 3-5. To this respect, several evidence have shown in MDD significant activation of inflammatory pathways, reflected by an increased level of pro-inflammatory cytokines, such as Interleukin-6 (IL-6), IL-1β, and TNFα 4, 5. Mitochondrial ROS production and mitochondrial damage have also been shown to be an important activators of inflammasome complex 6. Consistent with these findings, mitochondrial dysfunction biomarkers have been described in patients with MDD and animal models such as mitochondrial chain dysfunction, decreased levels of ATP, or reduced levels of coenzyme Q10 (CoQ10) 3, 7, 8. However, it is not clear how dysfunctional mitochondria can be involved in the MDD. Interestingly, significant mtDNA deletion has been associated with depression and reduced antioxidants levels 3, possibly linked to reported reduced mitochondrial biogenesis and antioxidants production in depressive patients. Our study examined this hypothesis to determinate the implication of mitochondrial biogenesis and antioxidants genes in the pathophysiology of MDD. Forty (40) patients with a diagnosis of melancholic depression (DSM-IV F33 ICD-10 CODE) in a first episode were collected from the Psychiatry Unit of Hospital Virgen Macarena in Seville, Spain. Diagnosis, according to diagnostic criteria of DSM-IV, was established by personal interview. The patients were also evaluated by the Beck Depression Inventory (BDI) (41.2 ± 5.9). The patients were included after diagnosis but before any antidepressant medication regimen. All patients were at least 18 years of age (Table 1), and either they gave informed consent to participate in this study. We included blood samples from twenty female healthy volunteers in the study matching the age range, ethnicity, gender, and demographics of the recruited patients. Previously, this study was approved by the ethical committee of our institution, and protocol has been carried out according to the Declaration of Helsinki. For statistical analyses, we used the SPSS package for Windows (SPSS, Chicago, IL). Data represent the mean ± SD. One-way ANOVA was used for statistical analysis of differences observed between numeric parameters of all groups using an all-pairwise multiple-comparison procedure (Tukey's test) for correction. The level of significance was set at P < 0.05. Forty patients with MDD and twenty healthy people (Control group) were included in the study. There were no statistical differences between groups by age or sex (Table 1); however, we observed increased levels of the BDI score (41.2 ± 5.9) in patients with MDD compared to the control group (4.9 ± 3.2), (P < 0.001). To clarify the possible mechanisms of mitochondria in the pathophysiology of MDD, we performed expression analysis for genes related to inflammation and inflammasome response, mitochondrial biogenesis, and antioxidant defense in blood monocyte cells (BMCs). BMCs from patients with MDD showed up-regulation of inflammation gene expression (IL-6 and TNF-α, P < 0.001) with no differences in IL-8 expression (Figure 1A) and inflammasome-related genes (NLRP3 and IL-1β, P < 0.001) (Figure 1B). Genes linked to mitochondrial biogenesis (PGC-1α, TFAM, NRF1, P < 0.001) were observed down-regulated (Figure 1C). Additionally, we observed down-regulated antioxidants gene expression (CuZnSOD and MnSOD, P < 0.001) (Figure 1D), accompanied with increased levels of mitochondrial ROS production (Figure 1E). To assess the functional consequences of a reduced mitochondrial biogenesis, ATP levels, as an indicator of cellular bioenergetics and well-being status, was determined. As shown in Figure 1F, BMCs showed a significant decrease in ATP levels, suggesting a reduced mitochondrial capacity in patients with MDD. The present study demonstrates a reduced mitochondrial biogenesis gene expression in BMCs from patients with MDD. As good mitochondrial function, and therefore energy production, is important for healthy cell activity, cells with decreased mitochondrial functional often show altered glycolysis as compensation. In mitochondrial dysfunction conditions, cells have catabolic changes in glucose metabolism affecting the Krebs cycle and going to anaerobic glycolysis, with a lactate accumulation as a result, and accordingly increased levels of lactate have been observed in MDD 9 showing a bio-energetic mitochondrial dysfunction. In this sense, mitochondrial dysfunction with bio-energ