A quarterly publication of the Autism Research Institute

The Autism Research Review International is quarterly publication of the Autism Research Institute

Summer, 2017 | Number 3, Volume 31

Ancient mitochondrial DNA variants may affect autism risk, lead to metabolic therapies

Variations in mitochondrial DNA (mtDNA) originating during ancient times may play a significant role in autism spectrum disorders (ASD), a new study reports. 

Mitochondria are the “power plants” of cells. They contain their own DNA, which codes for genes controlling cellular energy production, and these genes exchange signals with nuclear DNA. 

Douglas Wallace discovered in 1980 that human mtDNA (unlike nuclear DNA) is inherited only through the mother. Since then, he and his team have reconstructed patterns of worldwide human migrations over hundreds of millennia, identifying haplogroups—groups defined by differences in their mtDNA—that represent major branch points in evolution. 

In the current study, Wallace and his team, including lead researcher Dimitra Chalkia, analyzed the mtDNA of 1,624 individuals with ASD and 2,417 of their parents and siblings. Participants came from 933 families participating in the Autism Genetic Resource Exchange. 

The researchers found that participants in haplogroups designated as I, J, K, X, T, and U—collectively representing approximately 55 percent of the total European population—had an elevated risk of ASD compared to the most common European haplogroup, HHV. Asian and Native American haplogroups A and M also had an increased ASD risk. 

Wallace says these findings demonstrate that “a person’s vulnerability to ASD varies according to their ancient mitochondrial lineage.” He notes that mtDNA haplogroups originated in different areas and adapted to local environments. Later changes, such as migration or dietary changes, could create a mismatch between a mtDNA haplotype and an individual’s environment, resulting in a greater risk for certain diseases. 

Wallace’s team also notes that mtDNA’s role in energy production is crucial and that the brain is particularly vulnerable to even mild energy deficiencies because of its high mitochondrial energy demand. Studies by the team have shown that mitochondrial dysfunction can alter the balance between inhibition and excitation in the brain, a phenomenon seen in autism and other neuropsychiatric disorders (see related article on page 1). 

Wallace comments, “There may be a bioenergetic threshold,” theorizing that individuals vulnerable to ASD because of their mtDNA variants may be pushed over this threshold by environmental insults or the presence of other gene variants linked to ASD. 

He also notes that mtDNA variants may help to explain why more males than females develop ASD. Leber hereditary optic neuropathy (LHON), a condition known to result from mtDNA mutations, also affects more males than females. Wallace speculates that estrogen may increase beneficial antioxidant activity, helping to protect females from mtDNA-associated diseases. 

Wallace concludes that the findings of the study may help lead to therapeutic approaches. “There is increasing interest in developing metabolic treatments for known mtDNA diseases such as LHON,” he says. “If ASD has a similar etiology, then these same therapeutic approaches may prove beneficial for ASD.”


“Association between mitochondrial DNA haplogroup variation and autism spectrum disorders,” Dimitra Chalkia, Larry N. Singh, Jeremy Leipzig, Maria Lvova, Olga Derbeneva, Anita Lakatos, Dexter Hadley, Hakon Hakonarson, and Douglas C. Wallace, JAMA Psychiatry, August 23, 2017 (online). Address: Douglas Wallace, [email protected]


“Altered mitochondria associated with increased autism risk,” news release, Children’s Hospital of Philadelphia, August 23, 2017.