Lower Availability of Mitochondrial Complex I in Anterior Cingulate Cortex in Autism: A Positron Emission Tomography Study.

Scientists used brain scans to look at how well energy-producing parts of brain cells (mitochondria) work in autistic adults. They found that one brain area important for social behavior had less efficient energy production in autistic people compared to non-autistic people. Those with poorer energy production in this area also had more difficulty with social communication. This helps explain why some autistic people may have challenges with social skills.

This case-control PET imaging study examined mitochondrial function in the brains of 23 high-functioning autistic males compared to 24 typically developing controls. Using a specialized radioligand that binds to mitochondrial complex I, researchers found significantly reduced mitochondrial availability specifically in the anterior cingulate cortex of autistic participants. This reduction correlated with more severe social communication deficits. The study provides direct evidence of mitochondrial dysfunction in living autistic brains, supporting previous findings from postmortem studies.

The research suggests mitochondrial complex I could be a potential therapeutic target for autism core symptoms.

Findings suggest mitochondrial complex I dysfunction may contribute to autism pathophysiology, particularly social communication difficulties. This opens potential therapeutic avenues targeting mitochondrial function, though replication in larger, more diverse samples including females and varying autism presentations is needed before clinical application.

Small sample size (23 vs 24), male-only participants, limited to high-functioning autism without comorbidities, cross-sectional design prevents causal inferences, and potential selection bias from excluding participants with psychiatric comorbidities or medication use.

Mitochondrial dysfunction has been implicated in the pathophysiology of autism spectrum disorder (ASD) in previous studies of postmortem brain or peripheral samples. The authors investigated whether and where mitochondrial dysfunction occurs in the living brains of individuals with ASD and to identify the clinical correlates of detected mitochondrial dysfunction. This case-control study used positron emission tomography (PET) with 2--butyl-4-chloro-5-{6-[2-(2-[F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([F]BCPP-EF), a radioligand that binds to the mitochondrial electron transport chain complex I, to examine the topographical distribution of mitochondrial dysfunction in living brains of individuals with ASD. Twenty-three adult males with high-functioning ASD, with no psychiatric comorbidities and free of psychotropic medication, and 24 typically developed males with no psychiatric diagnoses, matched with the ASD group on age, parental socioeconomic background, and IQ, underwent [F]BCPP-EF PET measurements.

Individuals with mitochondrial disease were excluded by clinical evaluation and blood tests for abnormalities in lactate and pyruvate levels. Among the brain regions in which mitochondrial dysfunction has been reported in postmortem studies of autistic brains, participants with ASD had significantly decreased [F]BCPP-EF availability specifically in the anterior cingulate cortex compared with typically developed participants. The regional specificity was revealed by a significant interaction between diagnosis and brain regions. Moreover, the lower [F]BCPP-EF availability in the anterior cingulate cortex was significantly correlated with the more severe ASD core symptom of social communication deficits.

This study provides direct evidence to link in vivo brain mitochondrial dysfunction with ASD pathophysiology and its communicational deficits. The findings support the possibility that mitochondrial electron transport chain complex I is a novel therapeutic target for ASD core symptoms.