Transcriptomic Analysis Reveals Synaptic Dysregulation and Mitochondrial Dysfunction in Autism Spectrum Disorder

This study aims to investigate the molecular relationship between mitochondrial dysfunction and synaptic dysregulation in Autism Spectrum Disorder (ASD) through transcriptomic analysis, focusing on gene expression changes and disrupted pathways related to synaptic abnormalities and metabolic disruption. Transcriptomic data from peripheral blood samples in the GSE18123 dataset were analyzed to identify transcriptional changes associated with ASD. The analysis focused on 1,205 neurodevelopmental genes, with differential expression analysis conducted to compare gene expression between ASD and neurotypical control (NC) groups. Functional enrichment analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways mapped disrupted biological processes. Protein–protein interaction (PPI) networks were constructed to highlight central regulatory hubs, while gene co-expression analyses were employed to examine coordinated dysregulation across synaptic and metabolic networks. A total of 27 differentially expressed genes were identified, with 22 showing upregulation, suggesting increased molecular activity. Enrichment analyses highlighted the dysregulation of synaptic signaling pathways and mitochondrial oxidative phosphorylation, revealing a mechanistic link between metabolism disruption and synaptic abnormalities. PPI network analysis identified central regulatory hubs, including DKK1 and CYCS, highlighting intricate interactions between synaptic and mitochondrial pathways. Co-expression analysis demonstrated correlations within metabolic and synaptic functional modules, indicative of coordinated transcriptional dysregulation in ASD. This analysis uncovers a distinct molecular signature in ASD, emphasizing the convergence of synaptic abnormalities and metabolic disruption. The findings provide valuable insights into the pathophysiology of ASD and highlight potential targets for biomarker development and therapeutic strategies. • A comprehensive transcriptomic analysis elucidates a critical convergence of mitochondrial dysfunction and synaptic dysregulation, offering novel mechanistic insights into the pathophysiological landscape of ASD. • The identification of 27 differentially expressed genes, predominantly upregulated, underscores pervasive molecular dysregulation within essential pathways, particularly those governing synaptic signaling and energy metabolism, indicative of a hypermetabolic state in ASD. • Prominent regulatory hubs, including DKK1 and CYCS, emerge within enriched pathways of oxidative phosphorylation and synaptic signaling, positioning them as prospective targets for therapeutic intervention and advancing the search for reliable biomarkers in ASD.