Mitochondria are more than the powerhouses of the cell. They seem to have their hands in everything: heart disease, diabetes, cancer, and even neurological disorders such as autism.

Clinicians primarily rely on behavior patterns to diagnose autism. Despite its heritability, few people with autism have a shared disorder-causing mutation. But researchers are starting to identify the molecular underpinnings of the disorder. 

Neurologist Richard Frye has been demystifying the connection between mitochondrial dysfunction and autism for nearly a decade with his research at Phoenix Children’s Hospital. His latest study published in Translational Psychiatry  builds on growing evidence that changes in mitochondrial metabolism and morphology may contribute to autism development and severity (1).

“While we already know that there are abnormalities in the genes of the mitochondria in some individuals with autism, this study suggests that there are abnormalities in the function of mitochondria, and that this functional change can be seen in the shape or morphology of the mitochondria in cultured fibroblasts of children with autism,” Ann Neumeyer, an autism researcher and neurologist at Harvard Medical School who was not involved in this study, wrote in an email.

Frye, who led the new study, was initially interested in helping children with learning disabilities such as dyslexia during his residency and fellowship at Harvard University in the early 2000s. 

“I didn’t find autism; autism found me,” Frye said. “A lot of the time, families didn’t come to the doctor for learning disabilities, but what they were coming to the doctor for was for autism. All these families and kids diagnosed with autism — they didn’t know what caused it, and they really didn’t know what to do. It interested me as a neurologist."

Frye felt like he was making a difference in his patients’ lives as a clinician, but he knew that he could make an even greater impact if he could improve treatments. After noticing that several patients with autism also had mitochondrial disorders, he started researching the connection between autism and mitochondrial function. He expected to find deletions in key metabolic genes and unproductive mitochondria, which appear in canonical mitochondrial disorders like Leigh Syndrome. To his surprise, the mitochondria in patient-derived cells were working overtime, functioning 200% more than expected (2-3).

“When you are working 200% more than normal, if you put a little bit of stress in there, you fall apart easily. It’s not that much of a surprise. When people work around the clock, they are tired too. It’s like the mitochondria are always at the edge of burnout,” said Frye.

In his latest study, Frye set out to learn if changes in mitochondrial output correlated with mitochondrial morphology. Mitochondria are not the static beans depicted in our textbooks. Rather, they are dynamic organelles that merge and dissociate to form large mitochondrial networks. 

When cells demand more ATP, mitochondria fuse together to combine forces and increase output. If cells become more dependent on glycolysis for energy production, mitochondria fragment and wind down their energy production. For example, cells with limited access to oxygen and highly proliferative cell types, such as stem cells, usually depend primarily on glycolysis and contain fragmented mitochondria. 

Frye and his collaborators measured the activity of key mitochondrial metabolic enzymes in the electron transport chain and correlated that activity with how fragmented or fused mitochondria appeared in fibroblasts from patients with and without autism. They found that cells obtained from autism patients with severe symptoms had more fused mitochondria with complex branching patterns than patients with mild symptoms. Cells from patients with mild symptoms held mitochondria with morphology similar to control cells derived from patients without autism. Patients with more complex mitochondrial morphology experienced increased social withdrawal, hyperactivity, and stereotyped movements.

“We’ve really started to verify that there is this type of mitochondrial dysfunction in autism that’s real and that’s distinct from mitochondrial disease,” said Frye. “This isn’t a fixed mitochondrial defect. This is more of a dynamic mitochondrial defect. The promising thing here is that if you can change that dynamic, the mitochondria could work and stay within its boundaries.”

“It is exciting to think that the findings from this study might have implications for future treatment of autism,” Neumeyer said, but she noted that the research was done in fibroblasts rather than cells more relevant to the autism phenotype such as neurons. “The authors need to look at cultured cells from not just dermal or skin cells, but other tissues in children with autism [and controls] and then further investigate the relationship between shape and mitochondrial function [respiratory enzyme activity] to verify that this change is seen in other cell types, and not just in isolated dermal fibroblasts.” 

Frye is also interested in validating his results in other cell types, but obtaining patient cells can be challenging. Rather than isolating cells from patients, he is slowly developing protocols to reprogram patient-derived fibroblasts into induced pluripotent stem cells, which he can use to produce virtually any cell of interest. 

Frye doesn’t only want to look at other cell types though. He hopes that his work inspires others to consider the role mitochondria may play in disease. “I think it’s opening a box, and I don’t think it’s only autism. I think there are a lot of other diseases out there [involving mitochondria],” said Frye.

Check out this infographic and video to learn more about mitochondrial dynamics and their role in autism.

References

1. Frye, R.E. et al. Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder. Transl Psych  11, 527 (2021).
2. Rose, S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psych  5, e26 (2015).
3. Rose, S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines in a well-matched case control cohort. PLoS ONE  9, e85436 (2014).