Investigation of mitochondrial DNA copy number in patients with major depressive disorder
Introduction
Major depressive disorder (MDD) is a very common psychiatric disorder (Disease et al., 2016). Because the pathophysiology of MDD is not yet clearly understood, it is necessary to explore the biological mechanisms associated with MDD. Beyond studies assessing the neurochemical factors associated with MDD, many studies have investigated neurotrophic factors, neuroplasticity, and mitochondrial dysfunction to propose biological hypotheses of MDD (Duman, 2002; Duman et al., 1997; Manji et al., 2012).
Mitochondria play a primary role in the brain as an energy-generating intracellular organelle that performs the oxidative phosphorylation of adenosine triphosphate (ATP), which is a major source of energy. It is also important for intracellular processes associated with signal transduction, neuronal survival, and neuronal plasticity (Frye and Rossignol, 2011). Mitochondrial dysfunction may affect key cellular processes due to impairments in cellular resilience and synaptic plasticity (Manji et al., 2012; Schloesser et al., 2009) and has also been associated with psychiatric illnesses such as bipolar disorder, MDD, schizophrenia, and anxiety disorder (Jou et al., 2009; Rezin et al., 2009; Schapira, 2012; Shao et al., 2008).
A variety of studies have proposed that there is a possible link between depression and mitochondrial dysfunction. Structured psychiatric evaluations of patients with mitochondrial disease have shown that approximately 50% of these patients have lifetime MDD prevalence (Anglin et al., 2012; Fattal et al., 2007; Inczedy-Farkas et al., 2012; Koene et al., 2009; Mancuso et al., 2013). Furthermore, it has been reported that the deletion of mitochondrial DNA (mtDNA) in pediatric patients with a mitochondrial disorder is associated with mild-to-moderate unipolar depression (Koene et al., 2009). On the other hand, there are decreases in the intracellular pH and phosphorylated creatine levels during the depressed phase of bipolar disorder. Conversely, brain pH levels increase in response to triacetyluridine, which is a precursor of uridine that improves mitochondrial function, when administered to patients with bipolar disorder during the depressive phase of bipolar disorder (Jensen et al., 2008; Kato and Kato, 2000; Moore et al., 1997). Taken together, these findings suggest that triacetyluridine improves the symptoms of depression by improving mitochondrial function. Muscle biopsies performed on patients with MDD revealed a decrease in the rate of mitochondrial ATP production compared to the control group (Gardner et al., 2003).
It is possible to indirectly assess mitochondrial function by measuring mtDNA copy numbers. Cells requiring high energy, such as heart cells, skeletal muscle cells, and neurons, require large amounts of ATP and maintain a high mtDNA copy number (Moyes et al., 1998). mtDNA copy number is considered to be a marker of mitochondrial energy function (Clay Montier et al., 2009; Lee and Wei, 2005; Moyes et al., 1998). Abnormal mtDNA copy numbers have been reported to be associated with several types of mental illness (Bersani et al., 2016; Li et al., 2015; Yoo et al., 2017). In particular, several studies have investigated the association between MDD and mtDNA copy number. Some studies found that the mtDNA copy number was higher in patients with MDD (Nicod et al., 2016; Tyrka et al., 2016). On the contrary, others reported a lower mtDNA copy number in peripheral blood leukocytes of patients with MDD (Chang et al., 2015) or no significant differences in mtDNA copy number between patients with MDD and healthy controls (He et al., 2014; Lindqvist et al., 2018). It has been reported that the leukocyte mtDNA copy number is reduced during a depressive episode of bipolar disorder compared to controls (Wang et al., 2018). Taken together, these findings suggest that mtDNA copy number studies using the peripheral blood of patients with MDD have produced inconsistent results.
Several types of mechanisms may regulate the contents of mtDNA. Epigenetic change is one of the mechanisms that control mtDNA copy number (Kelly et al., 2012). The nuclear genes associated with the regulation of mtDNA expression include mitochondrial transcription factor A, mitochondrial specific DNA polymerase γ, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and it is important to note that DNA methylation has been studied at these sites (Barres et al., 2009; Choi et al., 2004; Kelly et al., 2012). PGC1α is a nuclear gene that mediates the biogenesis of mitochondria (Lehman et al., 2000) and the PGC1α protein is a transcriptional coactivator that regulates genes involved in energy metabolism, including mitochondrial-associated proteins and transcriptional factors, by activating nuclear receptors, especially peroxisome proliferator-activated receptors (PPARs) (Jarvis and Lopez-Juez, 2013; Liu et al., 2007). Clinical trials have shown that PPAR agonists effectively improve symptoms in patients with MDD (Kashani et al., 2013; Lin et al., 2015) and PGC-1α has been shown to be associated with depression-like behavior in animal models (Agudelo et al., 2014; Glombik et al., 2015). PGC1α expression in skeletal muscle is protective against the induction of depressive symptoms in a mouse model of chronic mild stress (Agudelo et al., 2014). PGC1α mRNA levels are lower in patients with MDD than healthy controls (Ryan et al., 2018). Methylation in the PGC1α promoter leads to long-lasting changes in PGC1α transcription and decreases in PGC1α expression that reduces the expression of mitochondrial genes (Barres et al., 2009; Scarpulla, 2008). Thus, it can be hypothesized that changes in the amount of mtDNA may be related to methylation in the PGC1α promoter in MDD. mtDNA may also undergo epigenetic modulations associated with aging and the development of disease (Blanch et al., 2016; Mawlood et al., 2016; Zheng et al., 2016). Changes in mtDNA methylation have been investigated in the displacement loop (D-loop), NADH dehydrogenase subunit 6 (ND6), and cytochrome C oxidase (CO1) regions (Pirola et al., 2013; Sanyal et al., 2018; Tong et al., 2017), and the replication of mitochondria is known to occur in the D-loop region of mitochondria (Clayton, 2000). Although this has been analyzed in several studies to identify its biological characteristics, contradictory results have been reported regarding the role that methylation in the D-loop plays in disorders such as Alzheimer's disease. DNA methylation levels in the mtDNA D-loop region of patients with late-onset Alzheimer's disease are lower than those of control subjects (Stoccoro et al., 2017) but higher in patients with early-onset Alzheimer's disease (Blanch et al., 2016).
Several studies have suggested that aberrant epigenetic mechanisms associated with MDD pathogenesis may cause changes in gene expression and be related to disease (Byrne et al., 2013; Na et al., 2014; Numata et al., 2015). However, little is known about the epigenetic modifications associated with mitochondrial content in MDD. Thus, it was hypothesized in the present study that nuclear DNA, PGC1α, and the mtDNA, D-loop would regulate mitochondrial content via epigenetic regulations.
Here, peripheral blood samples were obtained to compare the mtDNA copy numbers of patients with MDD and control subjects to determine whether mitochondrial dysfunction contributes to the pathophysiology of patients with MDD. Additionally, DNA methylation ratios in the D-loop region and PGC1α promoter were examined to identify which factors might lead to changes in the mtDNA copy number.
Section snippets
Subjects
Subjects for the present study were gradually recruited from among patients who routinely visited the outpatient psychiatric clinic of Eulji General Hospital and several other psychiatric clinics in the Republic of Korea. Patients with MDD were diagnosed by at least two psychiatrists according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). For the final diagnosis of each patient, the psychiatrists reviewed medical records and reached a
Demographic and clinical characteristics (Table 1)
This study included 118 patients with MDD. Of them, 50 (42.4%) had a single episode of MDD and 68 (57.6%) had recurrent MDD. The mean age was 47.6 ± 16.7 years, the mean duration of disease was 7.0 ± 9.7 years, and 18 patients (15.3%) had a history of suicide attempts.
Comparisons of mtDNA copy numbers and metDNA/unmetDNA ratios between the MDD and control groups (Table 2)
The mtDNA copy number of the MDD group was significantly higher than that of the control group (p < 0.001; Fig. 1). Single-episode MDD (p < 0.001) and recurrent MDD (p < 0.001) patients differed significantly from the control
Discussion
The present study demonstrated that the peripheral blood samples of patients with MDD had a higher mtDNA copy number than those of control subjects; these results were robust regardless of whether an individual had single-episode or recurrent MDD. Previous studies investigating mtDNA copy number in individuals diagnosed with MDD or showed depressive symptoms have yielded inconsistent results. Similar to the present findings, some studies have reported a higher mtDNA copy number in MDD cohorts (
Declaration of Competing Interest
The authors report no conflicts of interest.
Acknowledgment
This research was supported by EMBRI Grants 2018 from the Eulji University (2018EMBRISN0002) and the Bio & Medical Technology Development Program (No. 2016M3A9B694241) through the National Research Foundation of Korea (NRF) funded by MSIP.
References (84)
- et al.
Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression
Cell
(2014) - et al.
Non-CpG methylation of the PGC-1alpha promoter through dnmt3b controls mitochondrial density
Cell Metab.
(2009) - et al.
Differential associations of specific depressive and anxiety disorders with somatic symptoms
J. Psychosom. Res.
(2015) - et al.
Mitochondrial dna copy number is reduced in male combat veterans with PTSD
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2016) - et al.
Altered mitochondrial DNA methylation pattern in Alzheimer disease-related pathology and in Parkinson disease
Am. J. Pathol.
(2016) - et al.
Molecular signatures of major depression
Curr. Biol.
(2015) - et al.
In vitro methylation of nuclear respiratory factor-1 binding site suppresses the promoter activity of mitochondrial transcription factor a
Biochem. Biophys. Res. Commun.
(2004) - et al.
Number matters: control of mammalian mitochondrial DNA copy number
J. Genet. Genom.
(2009) - et al.
Abnormal glucose tolerance, white blood cell count, and telomere length in newly diagnosed, antidepressant-naive patients with depression
Brain Behav. Immun.
(2013) - et al.
Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients
J. Affect. Disord.
(2003)
Maternal stress predicts altered biogenesis and the profile of mitochondrial proteins in the frontal cortex and hippocampus of adult offspring rats
Psychoneuroendocrinology
Brain bioenergetics and response to triiodothyronine augmentation in major depressive disorder
Biol. Psychiatry
Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression
Psychoneuroendocrinology
Leukocyte mitochondrial DNA (mtDNA) content is associated with depression in old women
Arch. Gerontol. Geriatr.
Major depression in adolescent children consecutively diagnosed with mitochondrial disorder
J. Affect. Disord.
Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress
Int. J. Biochem. Cell Biol.
Adjuvant pioglitazone for unremitted depression: clinical correlates of treatment response
Psychiatry Res.
Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism
Nature
A genome-wide association study in the genetic analysis of idiopathic thrombophilia project suggests sex-specific regulation of mitochondrial DNA levels
Mitochondrion
The amount of mitochondrial DNA in blood reflects the course of a depressive episode
Biol. Psychiatry
Hypomethylation of mitochondrial D-loop and ND6 with increased mitochondrial DNA copy number in the arsenic-exposed population
Toxicology
Mitochondrial dysfunction in bipolar disorder: evidence, pathophysiology and translational implications
Neurosci. Biobehav. Rev.
Mitochondrial diseases
Lancet
High levels of mitochondrial DNA are associated with adolescent brain structural hypoconnectivity and increased anxiety but not depression
J. Affect. Disord.
Alterations of mitochondrial DNA copy number and telomere length with early adversity and psychopathology
Biol. Psychiatry
Differential mitochondrial DNA copy number in three mood states of bipolar disorder
BMC Psychiatry
Psychiatric symptoms correlate with metabolic indices in the hippocampus and cingulate in patients with mitochondrial disorders
Transl. Psychiatry
Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage
Int. J. Neuropsychopharmacol.
Monozygotic twins affected with major depressive disorder have greater variance in methylation than their unaffected co-twin
Transl. Psychiatry
Mitochondria DNA change and oxidative damage in clinically stable patients with major depressive disorder
PLoS One
Transcription and replication of mitochondrial DNA
Hum. Reprod.
Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the global burden of disease study 2015
Lancet
Synaptic plasticity and mood disorders
Mol. Psychiatry
A molecular and cellular theory of depression
Arch. Gen. Psychiatry
Chronicity of depression and molecular markers in a large sample of Han Chinese women
Depress. Anxiety
Psychiatric comorbidity in 36 adults with mitochondrial cytopathies
CNS Spectr.
Decreased mitochondrial DNA copy number in the hippocampus and peripheral blood during opiate addiction is mediated by autophagy and can be salvaged by melatonin
Autophagy
Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis
Am. J. Clin. Nutr.
Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders
Pediatr. Res.
Tissue type-specific bioenergetic abnormalities in adults with major depression
Neuropsychopharmacology
Leukocyte mitochondrial DNA copy number in blood is not associated with major depressive disorder in young adults
PLoS One
Psychiatric symptoms of patients with primary mitochondrial DNA disorders
Behav. Brain Funct.
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2023, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :We found no relationship between mtDNAcn and the severity of depressive symptoms. This is in line with some studies that have shown no association between mtDNAcn and mood in patients clinically diagnosed with bipolar disorder (de Sousa et al., 2014) or major depressive disorder (Fernstrom et al., 2021a; He et al., 2014), or in a community sample (Verhoeven et al., 2018); though this contrasts with other studies that have shown a negative relationship between mtDNAcn and mood and psychotic symptoms (Angrand et al., 2021; Chung et al., 2019; Czarny et al., 2020). However, we found a trend towards a positive association between mtDNAcn and the duration of the depressive episode, similar to the result of a previous report showing a significant positive relationship between the duration of the depressive episode and mtDNAcn (Edwards et al., 2016).
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2023, European Journal of PharmacologyCitation Excerpt :In recent years, numerous studies have shown that mitochondrial dysfunction is closely related to depression (Bansal and Kuhad, 2016; Allen et al., 2021; Mishra et al., 2021; Simon et al., 2021). Previous studies have shown mitochondrial dysfunction in the brains of patients with depression and in animal models (Rezin et al., 2008; Karabatsiakis et al., 2014; Sahafi et al., 2018; Chung et al., 2019). The antidepressants improve depression-like behaviors by repairing mitochondrial function (Maes et al., 2012; Shu et al., 2019; Limanaqi et al., 2020).
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2022, Journal of Psychiatric ResearchCitation Excerpt :Increased oxidative stress in BD1 patients who have suffered several mood relapses triggers mitochondrial dysfunction. However, we found no significant correlation between mtDNA copy number and mood episode number in BD2 patients, in line with our earlier finding that MDD patients did not exhibit any significant correlation between mtDNA copy number and the number of mood episodes (Chung et al., 2019). BD2 patients experience more depressive episodes than BD1 patients, but the sum of BD1 hypomanic and manic episodes exceeds the number of BD2 hypomanic episodes (Karanti et al., 2019).
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2021, MitochondrionCitation Excerpt :Also, higher mtDNA copy number were reported in subjects with early life stress, anxiety, and substance use disorders (Tyrka et al., 2016). A study conducted in 118 MDD patients and 116 age and sex-matched control subjects showed high mtDNA copy number in peripheral blood samples of MDD patients (Chung et al., 2019). Further, increased mtDNA levels were found in the peripheral blood samples of 179 patients in primary health care with depression, anxiety, and stress-and adjustment disorders, as compared to 320 healthy controls (Wang et al., 2017).
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These author contributed to this study equally.