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

Authors

Dijie Liu, Kai Tao, Yuxia Wang, Ying Sun, Shiyong Wang

Published in

Molecular neurobiology. Volume 63. Issue 1. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

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.

PMID:
42467385
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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