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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Autism spectrum disorder (ASD) exhibits significant variability in treatment response.
• Conventional explanations for treatment non-response in ASD are insufficient.
• Mitochondrial dysfunction is an emerging factor in persistent non-response to ASD therapies.

Purpose of the Study:

• To review the role of the mitochondrial-epigenetic axis in ASD treatment non-response.
• To explore the link between mitochondrial stress, epigenetic modifications, and synaptic dysfunction in ASD.
• To discuss novel therapeutic strategies targeting mitochondrial and epigenetic pathways in ASD.

Main Methods:

• Literature review integrating multi-omics findings and preclinical evidence.
• Analysis of adaptive transcriptional programs (UPRmt, NRF2-ATF4) and epigenetic effectors (DNMTs, HDACs, EZH2).
• Examination of mitochondrial noncoding RNAs (mt-ncRNAs) in epigenetic regulation.

Main Results:

• Mitochondrial stress activates transcriptional programs that lead to epigenetic repression of neuroplasticity genes.
• Mitochondrial noncoding RNAs may contribute to locus-specific epigenetic regulation, impacting treatment responsiveness.
• The mitochondrial-epigenetic axis is associated with synaptic dysfunction and clinical heterogeneity in ASD.

Conclusions:

• A mechanistic framework links mitochondrial stress to epigenetic remodeling and domain-specific treatment non-response in ASD.
• Modulating mitochondrial stress and epigenetic repression offers potential for precision therapeutics in ASD.
• Further research into the mitochondrial-epigenetic axis is crucial for advancing ASD treatment strategies.