Autism Pathoetiology and Pathophysiology: Roles of STAT3 and NF-κB Dimer Interactions in Regulating the Mitochondrial Melatonergic Pathway in Placental, CNS, and Systemic Cells.

This review suggests that people with autism may have problems making melatonin (a hormone that helps with sleep and other body functions) in their brain and body cells. The researchers think this melatonin problem might help explain many autism features, including sleep issues, inflammation, and mitochondrial problems. They believe studying melatonin pathways could lead to better understanding and treatments for autism.

This review examines how the melatonin pathway may be central to autism pathophysiology. The authors propose that people with autism show suppressed melatonin production across brain and body cells, regulated by interactions between STAT3 and NF-κB proteins. The review integrates various autism-related factors including mitochondrial dysfunction, inflammation, stress hormones, and oxytocin, suggesting they all connect through melatonin regulation. The authors argue that understanding this mitochondrial melatonin pathway could provide insights into autism's diverse manifestations and inform future research directions and potential treatments.

The proposed melatonin pathway dysfunction could inform development of targeted interventions for autism. However, this theoretical framework requires validation through controlled research before clinical applications. The integrated model may guide future research into autism mechanisms and potential treatments.

This is a review paper that integrates existing research rather than presenting new experimental data. The connections between melatonin pathways and autism features are largely theoretical and require empirical validation through controlled studies.

People with autism spectrum disorders (ASD) show a relative suppression of the melatonergic pathway across CNS and systemic cells. The differential regulation of the mitochondrial melatonergic pathway may therefore be an important core aspect of ASD pathophysiology in all its manifestations. Recent data across diverse human cells show that the melatonergic pathway is powerfully regulated by interactions between signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), with the composition of the NF-κB dimer determining whether the melatonergic pathway is upregulated or downregulated. Diverse aspects of ASD pathoetiology and pathophysiology, including the aryl hydrocarbon receptor (AhR), microRNAs, suboptimal mitochondrial function, pro-inflammatory cytokines, glucocorticoid receptor, vagal nerve, and oxytocin, are all intimately linked to pineal and/or local melatonin regulation, indicating the relevance of the mitochondrial melatonergic pathway regulation in the pathoetiology and pathophysiology of ASD.

This article reviews and integrates diverse aspects of ASD pathoetiology and pathophysiology, with implications for future research and treatment.