Altered mitochondria associated with increased autism risk

August 23, 2017, Children's Hospital of Philadelphia

Mitochondria, the tiny structures inside our cells that generate energy, may play a key role in autism spectrum disorders (ASD). A provocative new study by Children's Hospital of Philadelphia (CHOP)'s pioneering mitochondrial medicine team suggests that variations in mitochondrial DNA (mtDNA) originating during ancient human migrations may play an important role in predisposition to ASDs.

"Our findings show that differences in are important in ASD," said study leader Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP. "Our team demonstrates that a person's vulnerability to ASD varies according to their ancient mitochondrial lineage."

Wallace and colleagues, including Dimitra Chalkia, Larry Singh and others, published their findings today in JAMA Psychiatry.

The scientists conducted a cohort study of genetic data from 1,624 patients and 2,417 healthy parents and siblings, representing 933 families in the Autism Genetic Resource Exchange (AGRE). The Center for Applied Genomics at CHOP had previously performed genome-wide association studies on this AGRE cohort, and partnered in this study.

Mitochondria contain their own DNA, distinct from the more familiar nuclear DNA (nDNA) inside the cell nucleus. The mtDNA codes for essential genes governing cellular energy production, and those genes exchange biological signals with nDNA to affect our physiology and overall health.

The current study analyzed single-nucleotide functional variants—base changes in the cohort's mtDNA that characterize mitochondrial haplogroups. Haplogroups are lineages of associated mtDNA variants that reflect the ancient migration patterns of early human bands that spread out of Africa to the rest of the world during prehistory. Based on his seminal 1980 discovery that the human mtDNA is inherited only through the mother, Wallace's surveys over the years, covering mtDNA variation among indigenous populations around the world, have permitted the reconstruction of human worldwide migrations and evolution patterns over hundreds of millennia.

The current study found that individuals with European haplogroups designated I, J, K, X, T and U (representing 55 percent of the total European population) had significantly higher risks of ASD compared to the most common European haplogroup, HHV. Asian and Native American haplogroups A and M also were at increased risk of ASD.

These mitochondrial haplogroups originated in different global geographic areas, adapted through evolution to specific regional environments. However, subsequent changes, such as migration, changes in diet, and other environmental influences, can create a mismatch between the physiology of a particular mtDNA lineage and the individual's environment, resulting in predisposition to disease. Additional nDNA genetic factors or environmental insults may further reduce an individual's energy output until it is insufficient to sustain normal brain development and function, resulting in disease.

As the wiring diagram for cellular power plants, mtDNA is crucial in supplying energy to the body. The brain is particularly vulnerable to even mild energy deficiencies because of its high mitochondrial energy demand. Wallace's previous studies have shown that can disturb the delicate balance between inhibition and excitation in brain activity—a crucial factor in ASDs and other neuropsychiatric disorders. "There may be a bioenergetic threshold," says Wallace, adding that an individual already predisposed to ASD based on their mitochondrial haplogroup may be pushed below that threshold by the chance occurrence of additional genetic variants or environmental insults.

The striking tendency for ASD to occur more frequently in males than females may reflect another peculiarity of mitochondrial genetics, added Wallace. Males are four times more likely to suffer blindness from a well-known mtDNA disease, Leber hereditary optic neuropathy (LHON). The lower risk of blindness in females may arise from estrogen effects in mitochondria that increase beneficial antioxidant activity.

Wallace said that his team's finding that subtle changes in mitochondrial energetics are important risk factors in ASD suggests potential alternative approaches for therapy. He added, "There is increasing interest in developing metabolic treatments for known mtDNA diseases such as LHON. If ASD has a similar etiology, then these same therapeutic approaches may prove beneficial for ASD."

Explore further: Higher number of mitochondrial DNA-molecules can compensate for negative effects of mutations

More information: "Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders," JAMA Psychiatry (2017). DOI: 10.1001/jamapsychiatry.2017.2604

Related Stories

Higher number of mitochondrial DNA-molecules can compensate for negative effects of mutations

August 4, 2017
Male infertility can be caused by mutations in the DNA of mitochondria, the powerhouses of cells. By increasing the total DNA amount in mitochondria, scientists from the Max Planck Institute for Biology of Ageing in Cologne ...

Tiny mitochondria play outsized role in human evolution and disease

September 24, 2015
Mitochondria are not only the power plants of our cells, these tiny structures also play a central role in our physiology. Furthermore, by enabling flexible physiological responses to new environments, mitochondria have helped ...

For veterans with Gulf War Illness, an explanation for the unexplainable symptoms

September 11, 2015
One in four Gulf War veterans suffers from Gulf War Illness (GWI). The condition is characterized by unexplainable chronic fatigue, muscle pain and cognitive dysfunction and may be associated with exposure to chemicals, many ...

Unraveling the mystery of DNA attacks in cells' powerhouse could pave way for new cancer treatments

April 28, 2017
New research has unravelled the mystery of how mitochondria—the energy generators within cells—can withstand attacks on their DNA from rogue molecules.

Steadily rising increases in mitochondrial DNA mutations cause abrupt shifts in disease

October 22, 2014
New work by a pioneering scientist details how subtle changes in mitochondrial function may cause a broad range of common metabolic and degenerative diseases. Mitochondria are tiny energy-producing structures within our cells ...

Recommended for you

New methods find undiagnosed genetic diseases in electronic health records

March 15, 2018
Patients diagnosed with heart failure, stroke, infertility and kidney failure could actually be suffering from rare and undiagnosed genetic diseases.

Study finds that genes play a role in empathy

March 12, 2018
A new study published today suggests that how empathic we are is not just a result of our upbringing and experience but also partly a result of our genes.

Large-scale genetic study provides new insight into the causes of stroke

March 12, 2018
An international research consortium studying 520,000 individuals from around the world has identified 22 new genetic risk factors for stroke, thus tripling the number of gene regions known to affect stroke risk. The results ...

Study suggests some CpGs in the genome can be hemimethylated by design

March 9, 2018
A pair of researchers at Emory University has found that some CpGs in the genome can be hemimethylated by design, rather than by chance. In their paper published in the journal Science, Chenhuan Xu and Victor Corces describe ...

Intravenous arginine benefits children after acute metabolic strokes

March 9, 2018
Children with mitochondrial diseases who suffered acute metabolic strokes benefited from rapid intravenous treatment with the amino acid arginine, experiencing no side effects from the treatment. The diseases were caused ...

Inherited mutation leads to overproduction of EPO

March 9, 2018
A newly discovered hereditary mutation is responsible for an increased production of erythropoietin (EPO) in the blood. This mutation causes a messenger RNA (mRNA) that is not normally involved in the formation of proteins ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.