Peripheral biomarkers of mitochondrial dysfunction in adolescents with bipolar disorder

https://doi.org/10.1016/j.jpsychires.2020.02.009Get rights and content

Abstract

Background

Mitochondrial dysfunction has been implicated in the pathophysiology of bipolar disorder (BD). Impediment of mitochondrial oxidative phosphorylation results in a shift toward anaerobic respiration and lactate production. Elevated CNS lactate levels in adults with BD inform the need to evaluate lactate in peripheral samples and early in the course of BD. Furthermore, there exists a recent surge of investigations looking at circulating cell-free mitochondrial DNA (ccf-mtDNA) as a potential biomarker as they are released from cells under physiological stress, apoptosis, or bioenergetic compromise.

Objectives

To compare lactate and ccf-mtDNA, two different ways in assessing the mitochondrial health and function, in adolescents with BD versus healthy control adolescents (HC).

Methods

One-hundred and five adolescents (n = 64 BD, n = 41 HC) were included. Serum lactate level was measured using a commercially available colorimetric kit. Serum ccf-mtDNA concentration was measured using quantitative polymerase chain reaction from ccfDNA purified by commercially available spin columns. Diagnosis and mood symptoms were evaluated using semi-structured interviews.

Results

There is an increase in serum lactate level of adolescents with BD (1.319 ± 0.444 nmol/uL) versus HC (1.168 ± 0.353 nmol/uL; p = 0.043), but not ccf-mtDNA. Among BD adolescents, depression symptoms were negatively correlated with ccf-mtDNA levels (ρ = −0.289; p = 0.038) but loses significance when corrected for multiple comparison. Lactate was positively correlated with ccf-mtDNA in the overall sample (ρ = 0.201; p = 0.043). When examined by diagnosis, this association remained in BD (ρ = 0.273; p = 0.032), but not HC.

Conclusion

These preliminary results indicate that elevated lactate is observed even among adolescents early in their course of BD, that the association between lactate and ccf-mtDNA appears to be specific to BD, and that ccf-mtDNA is potentially associated with depression symptoms in adolescent BD. In addition, the effect of psychotropic medications used in the treatment of BD on peripheral lactate and ccf-mtDNA requires further investigation.

Introduction

Bipolar disorder (BD) is a chronic psychiatric disorder characterized by oscillation in mood including episodes of mania and depression, which comprise states of high and low mood/energy, respectively. The emergence of BD often occurs during adolescence (Kessler et al., 2005; Paus et al., 2008). In addition to high rates of psychiatric comorbidities, BD is associated with early-onset and excessive cardiovascular disease (CVD; Goldstein et al., 2015a). Despite increasing efforts, the molecular pathophysiology of BD, and its link with CVD and other comorbidities, is still unknown.

Mitochondrial dysfunction and compromised bioenergetics are hypothesized to play a key role in the pathophysiology of BD. A classical biological marker of mitochondrial dysfunction is the assessment of levels of lactate. Compromised mitochondrial oxidative phosphorylation, shifts the cellular bioenergetic system to anaerobic respiration and increases the level of lactate. Magnetic resonance spectroscopy show increased levels of lactate in the frontal lobe of adults with BD (Stork and Renshaw, 2005; Dager et al., 2004) and in the cerebrospinal fluid of adult BD patients (Yoshimi et al., 2016), and decreased levels of adenosine triphosphate (ATP) and phosphocreatine in the brains of patients with BD (Yuksel et al., 2015). Lactate has been used as a biomarker for mitochondrial diseases and can potentially offer a biologically relevant marker for BD (Boenzi and Diodato, 2018).

Another marker of mitochondrial health is the amount of mitochondrial DNA released by a cell. This quantification of mitochondrial DNA copy number is used as a measurement of mitochondrial biogenesis and cellular energetics (Clay Montier et al., 2009). Circulating cell-free mitochondrial DNA (ccf-mtDNA) levels reflect dysregulated homeostasis in lieu of cellular stress or apoptosis as small fraction of mitochondrial genome is released into circulation. The physiological function of ccf-mtDNA still remains unclear, however it is commonly used as a marker for cell damage and/or death, or bioenergetic compromise (Zhang et al., 2010). Although ccf-mtDNA were initially investigated in cancer studies, the potential to be a biomarker in psychiatric conditions has been increasingly growing in interest, and this is largely in respect to mitochondrial dysfunction.

Studying an adolescent BD population may serve as a window early on the disease and identification of biological pathways that have subtle changes, in comparison to more advance states of the illness. Current literature show that BD pathophysiology follow a neuroprogression framework (Berk, 2009; Schneider et al., 2012) and studying adolescents with BD would circumvent the allostatic load and medical comorbidities that is present in studying adults with BD. Thus, it is imperative to consider age-specific cohorts of psychiatric conditions, such as BD, to ultimately identify biological markers for the diagnosis and prognosis for effective therapeutic intervention. To the best of our knowledge, there have been no studies to date exploring lactate or ccf-mtDNA as potential biomarkers for BD diagnosis and/or symptoms in adolescents. Therefore, we sought out to measure serum lactate and ccf-mtDNA and compare the measurements between patients with BD and healthy control (HC). We hypothesize that peripheral levels of lactate will be elevated in adolescents with BD. We also hypothesize peripheral levels of ccf-mtDNA will be elevated in adolescents with BD. Using the demographic and clinical characteristics collected, exploratory analyses were also conducted to observe any effect such as BD symptomology and medication. For the exploratory analyses, we hypothesize that there will be a correlation between BD symptomology with peripheral lactate level. In addition, we hypothesize that there will be a correlation between BD symptomology with peripheral ccf-mtDNA level.

Section snippets

Subject selection and recruitment

Sixty-four adolescents diagnosed with either BD-I, BD-II or BD-not otherwise specified (NOS; operationalized based on the Course and Outcome of Bipolar Youth (COBY) study (Axelson et al., 2006)) were recruited from the Centre for Youth Bipolar Disorder at Sunnybrook Health Sciences Centre in Toronto, Canada. Forty-one HC adolescents were recruited from the Greater Toronto Area through public advertisement. All participants met the inclusion and exclusion criteria: age 13–21 years; able to

Clinical demographic characteristics

Summary of descriptive characteristics of the study population are found in Table 1. There were no significant differences between groups for number of male (X2 = 0.808; p = 0.432) nor for BMI (U = 1130; p = 0.282) and a statistically significant difference in age between groups (U = 732.50; p < 0.001). Despite the significant age difference, both groups fall under mid-to-late adolescence with an age range of 13–21 years of age for BD participants (with only 2 individuals over the age of 19)

Discussion

Lactate and ccf-mtDNA are molecular markers detectable in the periphery that assess and characterize mitochondrial dysfunction by two different endpoints. To the best of our knowledge, this is the first study to evaluate either of these markers in adolescents with BD. We found elevated lactate in adolescents with BD compared to HC, and a significant correlation between depression symptoms and ccf-mtDNA among adolescents with BD. Although no significant difference in ccf-mtDNA was present

CRediT authorship contribution statement

Hyunjin Jeong: Conceptualization, Data curation, Formal analysis, Methodology, Writing - original draft. Mikaela K. Dimick: Data curation, Writing - review & editing. Alysha Sultan: Data curation, Writing - review & editing. Angela Duong: Data curation, Writing - review & editing. Sarah Sohyun Park: Writing - review & editing. Dana El Soufi El Sabbagh: Writing - review & editing. Benjamin I. Goldstein: Investigation, Data curation, Project administration, Writing - review & editing. Ana C.

Declaration of competing interest

The authors declare no competing interest.

Acknowledgement

This study is funded by Canadian Institute for Health Research to A.C.A. We would like to thank the Centre for Youth Bipolar Disorder research staffs and the participants and their families for their vital contributions to our research.

References (38)

  • D. Axelson et al.

    A preliminary study of the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children mania rating scale for children and adolescents

    J. Child Adolesc. Psychopharmacol.

    (2003)
  • D. Axelson et al.

    Phenomenology of children and adolescents with bipolar spectrum disorders

    Arch. Gen. Psychiatr.

    (2006)
  • R.F. Bachmann et al.

    Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage

    Int. J. Neuropsychopharmacol.

    (2009)
  • I.G. Barbosa et al.

    Cytokines in bipolar disorder: paving the way for neuroprogression

    Neural Plast.

    (2014)
  • K. Becking et al.

    Inflammatory monocyte gene expression: trait or state marker in bipolar disorder?

    Int. J. Bipolar Disord.

    (2015)
  • M. Berk

    Neuroprogression: pathways to progressive brain changes in bipolar disorder

    Int. J. Neuropsychopharmacol.

    (2009)
  • S. Boenzi et al.

    Biomarkers for mitochondrial energy metabolism diseases

    Essays Biochem.

    (2018)
  • R.A. Bowen et al.

    Interferences from blood collection tube components on clinical chemistry assays

    Biochem. Med.

    (2014)
  • S.R. Dager et al.

    Brain metabolic alterations in medication-free patients with bipolar disorder

    Arch. Gen. Psychiatr.

    (2004)
  • Cited by (40)

    • Plasma circulating cell-free mitochondrial DNA in social anxiety disorder

      2023, Psychoneuroendocrinology
      Citation Excerpt :

      This difference was statistically significant across three separate time points and was not significantly affected by CBT treatment. Although there are previous reports of ccf-mtDNA in mood disorders (Fernstrom et al., 2021; Jeong et al., 2020; Kageyama et al., 2018; Lindqvist et al., 2018; Stertz et al., 2015), this is the first study to measure this biomarker in patients with anxiety disorders. Previous studies of mood disorders have produced variable results of high (Lindqvist et al., 2016, 2018), low (Fernstrom et al., 2021; Kageyama et al., 2018), or unchanged (Jeong et al., 2020; Stertz et al., 2015) plasma ccf-mtDNA in patients compared to healthy controls.

    View all citing articles on Scopus
    View full text