Peripheral Mitochondrial DNA Copy Number is Increased in Korean Attention-Deficit Hyperactivity Disorder Patients.

Johanna Inhyang Kim,Si Yeon Kim,Jae-Won Kim,Bung-Nyun Kim,Soon Ae Kim,Soo-Young Lee,Mira Park

doi:10.3389/fpsyt.2019.00506

Abstract

The involvement of mitochondrial dysfunction in the pathophysiology of attention-deficit hyperactivity disorder (ADHD) has been suggested in several reports. Mitochondrial DNA (mtDNA) copy number as well as methylation of the D-loop region and peroxisome-proliferator-activated receptor γ co-activator-1α (PPARGC1A) are considered biomarkers for mitochondrial dysfunction. We compared the mtDNA copy number and methylation ratio of the D-loop region and PPARGC1A between ADHD patients and controls and also among ADHD subtypes. The present study included 70 subjects with ADHD and 70 age- and gender-matched healthy controls (HCs). We measured the relative mtDNA copy number in peripheral blood cells using quantitative polymerase chain reaction (qPCR), and the methylation ratio was measured using methylation-specific PCR (MSP) after bisulfite conversion. The relative mtDNA copy number was significantly higher in ADHD patients than in HCs (p = 0.028). The mtDNA methylation ratio of PPARGC1A was decreased in ADHD patients compared with HCs (p = 0.008). After adjusting for IQ level, only the mtDNA copy number differed between the ADHD and HCs (p = 0.01). There was a significant difference in the methylation ratio of PPARGC1A among ADHD subtypes. These results suggest the possible involvement of mitochondrial dysfunction in the pathophysiology of ADHD. Further large cohort studies investigating the correlation between clinical markers and biomarkers of mitochondrial dysfunction are warranted.

Highlights

Attention-deficit hyperactivity disorder (ADHD) is a highly prevalent and persistent neurodevelopmental disorder characterized by developmentally inappropriate symptoms of inattention, hyperactivity, and/or impulsivity [1]
The intelligence quotient (IQ) level was lower in attention-deficit hyperactivity disorder (ADHD) patients than in healthy controls (HCs), but no differences in age, gender, maternal and paternal education levels, or family income were observed between the two groups
After adding IQ as a covariate, the statistical difference of the Mitochondrial DNA (mtDNA) copy number between the two groups remained significant (p = 0.01), but there was no significant difference in the DNA methylation ratio of the PPARGC1A promoter region and the D-loop region

Summary

Introduction

Attention-deficit hyperactivity disorder (ADHD) is a highly prevalent and persistent neurodevelopmental disorder characterized by developmentally inappropriate symptoms of inattention, hyperactivity, and/or impulsivity [1]. ADHD has an estimated heritability of 76% [2] and appears to be a complex polygenic disorder influenced by various genetic and environmental factors. Mitochondrial Dysfunction in ADHD of the genetic factors in ADHD [3]. Mitochondrial dysfunction is involved in the pathogenesis of various psychiatric disorders [5,6,7]. Mitochondria are specialized subcellular organelles that contribute to aerobic ATP generation through oxidative phosphorylation for energy metabolism [8]. It plays crucial roles in calcium signaling, which is involved in exocytosis, synaptic plasticity, and the generation of reactive oxygen species (ROS) in the brain [9, 10]. Mitochondria have been implicated in multiple neurodevelopmental processes central to synaptopathies, including neuronal differentiation [11], process outgrowth [12], cortical migration [13], and synaptogenesis [14]

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