Transcriptomic Signatures of Mitochondrial Dysfunction in Autism: Integrated mRNA and microRNA Profiling

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Abstract

This study explores how mRNA and microRNA (miRNA) expression profiles distinguish subtypes of autism spectrum disorder (ASD) defined by mitochondrial function. Using lymphoblastoid cell lines (LCLs) from boys with ASD are classified into two groups: those with abnormal (AD-A) and normal (AD-N) mitochondrial function. Prior work established that about a third of ASD-derived LCLs show excessive mitochondrial respiration and stress vulnerability—features divergent from both controls and classical mitochondrial disease. Through RNA-seq, we identified 24 differentially expressed genes (DEGs)(14 downregulated, 10 upregulated in AD-N vs. AD-A), implicating processes such as mRNA processing, immune response, cancer biology, and crucially, mitochondrial and nuclear activities. Notably, genes such as DEPTOR (an mTOR modulator) were upregulated in AD-A, highlighting dysregulation in the mTOR pathway—a central regulator of cellular metabolism, protein synthesis, autophagy, and mitochondrial function. miRNA analysis revealed 18 differentially expressed miRNAs (DEMs) upregulated and one downregulated in AD-N compared to AD-A. Several miRNAs (including hsa-miR-1273h-3p, hsa-miR-197-3p, and hsa-miR-199a-5p) targeted both the differentially expressed genes and pathways previously linked to ASD, such as mTOR, Cam Kinase II, and mitochondrial regulation. Enrichment analyses indicated involvement in transcription, ATP binding, and oxidative stress-response pathways, with the ECM receptor interaction pathway notably prominent. These molecular signatures support the idea that mitochondrial dysfunction in ASD is tied to specific disruptions in the mTOR and PI3K/AKT signaling axes, influencing autophagy, oxidative stress handling, and neuronal metabolism. The findings highlight a miRNA-mRNA network that may underpin mitochondrial dysfunction and ASD heterogeneity, suggesting avenues for subtype-specific biomarkers and targeted therapies that address energy metabolism and cellular stress in ASD.

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