Analysis of mitochondrial DNA replisome in autism spectrum disorder: Exploring the role of replisome genes.
Autistic kids carry extra mitochondrial DNA in cheek cells, yet the usual copy-machine genes look normal, so look upstream for the trigger.
01Research in Context
What this study did
Rojas et al. (2025) compared cheek cells from children with autism and neurotypical kids.
They measured mitochondrial DNA copy number, replisome gene activity, and oxidative stress markers.
The team wanted to know if the machinery that copies mitochondrial DNA is broken in autism.
What they found
Kids with autism had more mitochondrial DNA copies in their cheek cells.
Oxidative stress was also higher, but replisome gene expression stayed the same.
The main driver of extra mtDNA lies outside the genes tested here.
How this fits with other research
Ch'ng et al. (2015) pooled over 1,000 brain scans and also saw mitochondrial genes light up, so the mtDNA signal is not new.
Baker et al. (2025) looked at blood from adults with intellectual disability and found large mtDNA rearrangements instead of extra copies.
The two 2025 papers seem opposite, but one studied children with autism while the other studied adults with ID, so age and diagnosis explain the gap.
Eggleston et al. (2018) used the same cheek-cell approach and found saliva microbes, not genes, could flag autism, showing oral samples can yield usable biomarkers.
Why it matters
You now have a quick cheek swab marker—high mtDNA copy number—that may point to cellular stress in autism.
It does not tell you which replisome gene to target, but it can signal who might benefit from antioxidant or energy-support plans.
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02At a glance
03Original abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition often associated with mitochondrial dysfunction, including increased mitochondrial DNA (mtDNA) copy number and impaired energy production. This study investigates the role of the mitochondrial replisome-specifically, the genes TFAM, TWNK, POLG, and TOP1MT-in mtDNA replication and its potential contribution to ASD pathophysiology. We analyzed samples from the oral mucosa of children with ASD and typically developing (TD) controls, assessing mtDNA copy number, gene expression, and protein levels. Our findings revealed a significant increase in mtDNA copy number in the oral mucosa of ASD children, along with partially deleted mtDNA molecules. However, there were no significant changes in the expression of TFAM, TWNK, POLG, or MT-TL1 genes between ASD and TD samples. Additionally, TFAM protein levels, including monomeric, dimeric, and trimeric forms, did not differ significantly. We also observed increased oxidative stress and inflammatory markers in the oral mucosa of ASD children, suggesting that mitochondrial alterations may be linked to inflammation and oxidative damage in ASD. To further investigate the functional impact of TFAM, we overexpressed it in human HEK293 cells and cortical neurons (CN1.4). TFAM overexpression led to increased mtDNA copy number, cell proliferation, and ATP production in HEK293 cells, but did not significantly alter mitochondrial gene expression, protein oxidation, or mtDNA integrity. In CN1.4 neurons, TFAM overexpression increased mitochondrial membrane potential and length, indicating potential changes in mitochondrial dynamics. Overall, our study suggests that while mtDNA alterations are present in ASD, they are not directly driven by changes in mitochondrial replisome gene expression. These findings highlight the complexity of mitochondrial dysfunction in ASD and suggest the need for further investigation into the underlying molecular mechanisms.
Autism research : official journal of the International Society for Autism Research, 2025 · doi:10.1002/aur.3277