Exploring Mitochondrial DNA Copy Number in Italian Children with ADHD: Implications for Neurobiological Mechanisms

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition frequently accompanied by behavioral dysregulation. While genetic factors involving monoaminergic systems have been implicated, emerging evidence suggests a role for mitochondrial dysfunction in ADHD pathophysiology. Mitochondrial DNA copy number (mtDNA-cn), a surrogate marker of mitochondrial biogenesis and cellular energy demand, may reflect underlying neurobiological alterations and oxidative stress-related mechanisms relevant to ADHD.

We assessed mtDNA-cn in the peripheral blood of 56 Italian children and adolescents with ADHD and 27 age- and sex-matched healthy controls. ADHD symptoms and aggressive behavior were evaluated using DSM-5 criteria and the Conners' 3 Rating Scales. Genotyping was performed for MAOA (rs6323, rs1137070) and 5-HTT (rs4795541) polymorphisms.

ADHD patients showed significantly higher mtDNA-cn than controls (p = 0.002), supporting mitochondrial dysregulation. Comparing the ADHD patient subgroups with aggressive behavior and those without, a non-significant reduction in mtDNA-cn was observed in the first subgroup. Notably, individuals with the TT genotype (rs6323) or CC genotype (rs1137070) had significantly higher mtDNA-cn compared to controls with the same genotypes (p = 0.031). Similar increases were seen across all 5-HTT rs4795541 genotypes in ADHD patients.

Our findings suggest that mitochondrial alterations may contribute to ADHD pathophysiology. The association between mtDNA-cn and monoaminergic gene variants highlights a potential link between neurotransmitter metabolism, oxidative stress, and mitochondrial function. Thus, mtDNA-cn may serve as a peripheral biomarker and therapeutic target in ADHD.