Altered Co-Expression Patterns of Mitochondrial NADH-Dehydrogenase Genes in the Prefrontal Cortex of Rodent ADHD Models

Altered mitochondrial function is implicated in disorders characterized by prefrontal cortex activation deficits, including attention deficit hyperactivity disorder (ADHD). The expression of mitochondrial DNA-coded respiratory chain complex I genes (<i>ND1-ND6</i>) in the prefrontal cortex of ADHD animal models was estimated in the present study. ND gene expression was assessed in two publicly available datasets: GSE117357 (<i>Adgrl3</i> knockout mice) and GSE173926 (<i>MYT1L</i> heterozygous knockout mice). Additionally, we measured <i>NDs</i> gene expression via qPCR in dopamine transporter knockout (<i>DAT</i>-KO) rats and their heterozygous (<i>DAT</i>-Het) littermates. Transcriptomic analysis revealed consistent <i>ND1-ND6</i> expression profiles across both datasets, and co-expression among <i>ND</i> genes was significantly enhanced in ADHD models compared to wild-type controls. Whole-transcriptome analysis identified associations between <i>ND3</i> and <i>ND4L</i> expression and genes involved in neural tissue-specific processes, exclusively in ADHD models. In <i>DAT</i>-KO and <i>DAT</i>-Het rats, <i>NDs</i> gene co-expression increased. Furthermore, in <i>DAT</i>-Het rats, which do not exhibit hyperactivity, the upregulation of <i>ND4L</i> expression relative to wild-type littermates was demonstrated. The observed changes in mitochondrial complex I gene co-expression in ADHD models suggest mitochondria may serve as a prospective target for adjuvant therapy. These findings highlight the need for further investigation into mitochondrial contributions to ADHD pathophysiology.