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

Scientists studied cells from boys with autism to understand why some have problems with their cellular energy systems (mitochondria). They found specific genetic patterns that differ between children with normal and abnormal energy function. These patterns involve pathways that control cell growth and stress responses. The findings may help explain why autism affects people differently and could lead to more personalized treatments targeting energy problems in cells.

This study examined gene expression differences in cell lines from boys with autism, comparing those with abnormal versus normal mitochondrial function. Researchers identified 24 differentially expressed genes and 19 microRNAs that distinguish these groups. Key findings implicated the mTOR pathway, which regulates cellular metabolism and mitochondrial function. Genes like DEPTOR were upregulated in the abnormal mitochondrial function group.

Several microRNAs targeted both the identified genes and pathways previously linked to autism, including mTOR signaling. The results suggest that mitochondrial dysfunction in autism involves specific disruptions in cellular growth, autophagy, and stress response pathways, potentially explaining some of the heterogeneity observed in autism spectrum disorder.

Findings suggest potential for developing subtype-specific biomarkers and targeted therapies for autism cases with mitochondrial dysfunction. mTOR pathway modulators may represent therapeutic targets. However, validation in larger samples and demonstration of clinical utility are needed before translation to practice.

Sample size not reported. Study limited to lymphoblastoid cell lines from boys only, which may not reflect in vivo conditions or represent females with autism. Functional validation of identified pathways not demonstrated. Cross-sectional design cannot establish causality between molecular signatures and mitochondrial dysfunction.

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. This study explores how mRNA and microRNA (miRNA) expression profiles distinguish subtypes of autism spectrum disorder (ASD) defined by mitochondrial function. Lymphoblastoid cell lines (LCLs) from boys with ASD were classified into two groups: those with abnormal (AD-A) and normal (AD-N) mitochondrial function. RNA-seq compared mRNA and miRNA expression differences. 24 mRNA differentially expressed genes (DEGs) (14 downregulated, 10 upregulated in AD-N vs.

AD-A) were identified, 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, Calmodulin Kinase II, and mitochondrial regulation. Enrichment analyses indicated involvement regulation of cell growth and division, gene expression, immune regulation and cellular stress as well as mTOR signaling.

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 cell growth, autophagy, oxidative stress handling, and neuronal metabolism. The findings highlight a miRNA-mRNA regulatory 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.