Mitochondrial-Epigenetic Crosstalk in Autism Spectrum Disorder: Linking Cellular Stress to Synaptic Dysfunction and Treatment Resistance.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by striking heterogeneity in therapeutic outcomes, with a substantial subset of individuals showing limited or absent improvement in targeted behavioral domains following behavioral or pharmacological interventions. Traditional explanations for poor treatment response-such as receptor desensitization and pharmacokinetic variability-fail to capture the persistent, systems-level alterations underlying this phenomenon. Emerging evidence identifies mitochondrial dysfunction as a critical but underexplored contributor to persistent treatment non-response in ASD. Beyond energy failure, mitochondrial stress activates adaptive transcriptional programs (UPRmt, NRF2-ATF4) that recruit epigenetic effectors, including DNMTs, HDACs, and EZH2, leading to chromatin remodeling and repression of neuroplasticity-related genes. In parallel, mitochondrial noncoding RNAs (mt-ncRNAs) may participate in locus-specific epigenetic regulation, establishing a relatively stable transcriptional state that constrains treatment responsiveness. This review consolidates current insights into the mitochondrial-epigenetic axis in ASD, highlighting its association with synaptic dysfunction and clinical heterogeneity. We further discuss emerging strategies aimed at modulating mitochondrial stress and epigenetic repression, including mitochondria-targeted antioxidants, epigenetic modulators, and CRISPR/dCas9-based epigenome editing. By integrating recent multi-omics findings and preclinical evidence, we propose a mechanistic framework linking mitochondrial stress to epigenetic remodeling and domain-specific treatment non-response, with implications for precision therapeutics in ASD.