Meet the ‘mitomaniacs’ who say mitochondria matter in autism | Spectrum
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W.Allace – who was refused a scholarship earlier this year to continue his mouse studies on mitochondrial function in autism – does not allow himself to be dissuaded by difficulties. He believes that most forms of autism are associated with mitochondria, and that many genes associated with autism play an as-yet-undiscovered role in mitochondrial function. Some mouse models of autism support the latter idea. Mice missing a stretch of DNA called 22q11.2, an autism-related mutation, have both misshapen mitochondria and neurons with structural deficits, a 2019 study showed. Giulivi and her colleagues reported in 2012 that mice that under-express the autism-related PTEN gene also have low levels of a protein that the mitochondria use for energy.
Similarly, mice lacking FMR1, the fragile X syndrome gene, show signs of metabolic stress and reduced expression of two genes that help mitochondria fuse together, which they often need to do to meet energy needs Zhao and her colleagues showed in 2019. Findings such as This suggests that many underlying causes of autism lead to mitochondrial dysfunction, which makes the mitochondria a “central center” of the disease, says Jonas.
Some mitomaniacs also claim that mitochondria could help explain the many autism-related features and challenges that occur outside of the brain, such as gastrointestinal problems and motor problems. After all, practically all parts of the body depend on mitochondria to varying degrees. For example, mouse models of two different autism-related diseases have different body weights, burn calories differently, and have different metabolites in their blood than the control mice and the others, according to a study published in March.
Mitochondrial influence can even go beyond autism, says Novarino. “Sure, it looks like mitochondria and mitochondrial DNA are an emerging pathway or cause of autism, but I don’t think it’s specific to autism,” she says. “It’s an emerging part of brain development.”
Mitochondrial problems likely have the greatest impact during mid-fetal development, when autism is believed to occur. In one theory, congenital mitochondrial disease makes the developing brain more vulnerable to other environmental influences and causes changes that lead to autism, Gu says. “Somehow, their mitochondrial homeostasis isn’t as stable or robust as other children,” he says. “Any stress – it could be a virus, it could be environmental stress – can trigger this completely different development.”
Gu and his team are analyzing umbilical cord blood from 1,000 children with autism and mtDNA samples from their mothers to see whether the mutations occur prenatally. If so, the mutations are more likely to affect the condition. Preliminary results seem to support his 2016 results, Gu says.
For Fragile X syndrome, the researchers have a more specific hypothesis. Early in development, mitochondria have channels in their inner membranes that allow protons to escape, much like the hole near a sink, preventing the sink from overflowing. Later in development, the holes close, which leads to a change in metabolic processes. If this does not happen or if this happens too late, synapses may not form properly, as Jonas showed in human cells. And in fragile X-mice, the mitochondria remain leaky – and have to work particularly hard to keep the energy level stable, as Jonas and Levy have shown. “We think it’s a normal stage of development that just never got through,” says Jonas.
If so, it may be possible to treat the fragile X by closing that leak, which Jonas and her colleagues did by bathing mouse neurons in dexpramipexole, a drug that has been tested (unsuccessfully) in people with amyotrophic lateral sclerosis. The drug binds to the enzyme that synthesizes ATP, which can close the leak and thereby improve mitochondrial function, although the process is still unclear. Injecting fragile X mice with dexpramipexole reduced over-grooming and nest tearing, a proxy for repetitive behavior in humans.
Such treatment could also alleviate difficulties related to other forms of autism, says Jonas. The leak doesn’t appear to be directly related to the FMRP mutation, she says, and it’s likely that mitochondria are critical to early synapse development, a process that lays the foundation for the circuitry of the brain.
Another potential treatment for problems related to autism is a compound called M1, which promotes mitochondrial fusion. When Zhao treated her fragile X mice with M1, they became more social and had better memories. And in an unpublished work presented at the Society for Neuroscience 2021 meeting, researchers found that injecting Rett syndrome mice with the oral anesthetic dyclonine made the mice live longer and improve their mitochondrial function, as well as their breathing, motor skills and improved limb strength. These effects were comparable to the experimental increase in the expression of the antioxidant enzyme catalase in the animals.
Yet few drugs that target mitochondria are in human studies for Rett, Fragile X, or other forms of autism. As of now, the options are limited. “We don’t have many good solutions for mitochondria,” says Gargus. “That is the actual problem.”
Another problem is drawing a direct line from mitochondrial defects to autism. Jonas is investigating whether such defects, for example the persistent leak she describes, alter nuclear gene expression in neurons. She and her colleagues are also using cells and mice to investigate whether closing the leak with drugs could induce the brain to reform changed circuits. Zhao studies human neurons to better understand how FMR1 might regulate mitochondrial fusion; Your goal is to track down pathways that mitochondria connect to autism and thereby identify treatment goals.
