WeeklySA_AdminMETABOLISM: The body’s energy system may hold key to understanding condition, study shows…
By Special Correspondent
The brain and metabolism are in constant conversation. When that conversation goes wrong during critical windows of early development, autism spectrum disorder can result.
That’s the core insight from research at UC San Diego that positions cellular energy and metabolism as a central factor in brain development and autism risk.
Scientists have long struggled to explain how hundreds of different genetic and environmental causes produce similar autism symptoms. A model published in Mitochondrion reveals the answer lies in metabolism. More specifically, in how cells produce, use, and signal with energy molecules during the first years of life.
“The brain controls metabolism, and metabolism controls the brain,” explains Dr Robert Naviaux, who directs the Mitochondrial and Metabolic Disease Centre at UC San Diego School of Medicine. His team’s research identifies a cellular energy signaling system as a common denominator linking genetics, environmental exposures, immune function, and neurodevelopment in autism.
How Cellular Stress Signals Shape Brain Development
At the centre of this system sits a molecule called extracellular ATP, or eATP. When cells experience stress from infection, toxins, or inflammation, they release ATP outside the cell as a danger signal. This triggers a defensive response called the cell danger response, or CDR, which redirects cellular resources away from growth and toward protection.
In typical development, this stress response activates briefly when needed, then shuts off completely. But, in children who develop autism, the system can become activated repeatedly or persistently during a neuro-critical window spanning from late first trimester of pregnancy through the first 18-36 months of life.
The resulting metabolic changes rewire how the brain forms connections, how neurotransmitters are produced, and how the immune system and gut microbiome develop.
Cells that experience repeated stress during early development adapt in lasting ways. They alter the composition of their membranes, change how their mitochondria produce energy, and become hypersensitive to the very stress signals meant to protect them. These metabolic adaptations create a kind of cellular memory that persists long after the original triggers have passed.
This metabolic hypersensitivity explains several puzzling features of autism. Children with autism often show heightened responses to sensory stimuli—not just sounds and lights, but also foods, chemicals in the environment, and even changes in routine. Under this model, these sensitivities trace back to cells and neurons that have become metabolically primed to detect and respond to potential threats.
The model also explains why 75-95% of children with autism have additional medical conditions. Problems like gastrointestinal issues, sleep disorders, epilepsy, and immune dysfunction aren’t separate from autism—they’re different expressions of the same underlying metabolic disruption affecting different organ systems.
Mitochondria, the cellular powerhouses that produce energy, play a central role. Between 15% and 96% of children with autism show biomarkers or symptoms of mitochondrial dysfunction, not because they have primary genetic mitochondrial diseases, but because their mitochondria have adapted to chronic cellular stress. These adaptations make cells more fragile when exposed to additional stressors, a phenomenon researchers call “mitochondrial redox fragility.”
Three Factors Must Align
For autism to develop under this model, three factors must align. First, a child inherits genes that make their mitochondria and cellular signalling systems hypersensitive to environmental changes. These genetic variations affect how cells handle stress and release chemical signals.
No single gene determines the outcome on its own. Even strong single-gene conditions associated with autism show variable penetrance, with some increasing risk by 13-fold or more compared to the general population. Yet even these powerful genetic factors still require environmental and timing elements to tip the balance toward autism.
Second, the child experiences environmental exposures that activate the cell danger response during critical developmental windows. These triggers include air pollution, maternal fever during pregnancy, certain maternal auto-antibodies, metabolic conditions like gestational diabetes, or exposure to pesticides and other chemicals. Each of these factors disrupts mitochondrial function and activates stress signalling pathways.
The third factor is persistence or recurrence. When metabolic stress continues or returns repeatedly during the neuro-critical window—particularly across several months of that early developmental period—it changes the trajectory of brain development. This prevents the normal developmental shift from excitatory to inhibitory signalling that typically occurs in the first years of life.
Metabolism Rewires Multiple Body Systems
The metabolic effects cascade through multiple systems simultaneously. In the gut, chronic stress signalling changes which microbes can survive and thrive, altering the microbiome. The gut produces over 95% of the body’s serotonin, and disrupted gut metabolism affects this neurotransmitter system.
In the brain, metabolic stress activates immune cells called microglia and support cells called astroglia. These activated cells release inflammatory signals that alter how neurons form connections with each other.
The process of synaptogenesis—the formation of connections between neurons—is extremely active during the first years of life and requires enormous metabolic resources. When those resources are redirected toward cellular defence, typical brain wiring patterns don’t develop.
An autistic child playing with parent
The metabolic disruption also affects specific brain regions. The cerebellum, which contains some of the most metabolically active cells in the brain, shows consistent abnormalities in autism. Specialized inhibitory neurons called Purkinje cells can be lost during the critical developmental window, particularly in children who experience developmental regression.
In some brain regions, specialised structures called circumventricular organs lack a blood-brain barrier and constantly monitor chemicals in the blood. When the metabolic stress response makes these monitoring systems hypersensitive, children can develop multimodal sensory and chemical over-responsivity to non-threatening environmental stimuli.
Early Detection Through Metabolic Screening
The metabolic model opens new possibilities for early detection and prevention. Several screening methods can identify metabolic signatures of autism risk before symptoms appear. Analysis of maternal blood during pregnancy can predict autism risk with 90% accuracy by detecting metabolic patterns associated with chronic cellular stress. The patterns include decreased amino acid and fatty acid metabolism, reduced glutathione, and disrupted folate and B12 metabolism.
After birth, metabolic analysis of dried blood spots from newborn screening can identify infants at risk. Specialised hair analysis measuring how the body deposits metals over time can predict autism development with 81% accuracy in the first month of life.
These methods detect disruptions in metabolic phase synchronisation—the rhythmic coordination of cellular activities throughout the body that must occur for healthy development.
Testing for maternal autoantibodies during pregnancy can also identify high-risk pregnancies. Women who have two or more of a defined set of 10 autism-related autoantibodies face a 7.8-times increased risk of having a child who develops autism. These autoantibodies target proteins involved in mitochondrial function, metabolism, and cellular stress responses.
The research draws parallels to phenylketonuria, or PKU, a genetic metabolic disorder that once caused severe intellectual disability. PKU also follows a 3-hit pattern: genetic predisposition affecting amino acid metabolism, exposure to dietary phenylalanine, and persistence of toxic metabolites during development. With newborn screening and dietary management, over 90% of children born with PKU now lead normal lives.
The authors estimate that if early risks are identified and addressed, a meaningful share of autism cases—possibly 40-50%—might be preventable. This is a projection based on the model rather than a result already achieved.
The estimate derives from evidence that environmental triggers and prolonged stress activation are modifiable factors even when genetic predisposition exists.
Current treatment approaches focus on three areas: reducing environmental exposures that activate cellular stress, supporting metabolic resilience through nutrition and treatment of co-occurring conditions, and developing medications that can restore balance to hypersensitive signalling systems.
Treatment
One experimental class of drugs called antipurinergics targets the ATP signalling pathway that maintains chronic cellular stress. Animal studies and one small human trial have shown promising results, though larger trials are still needed to establish safety and efficacy. No antipurinergic treatment for autism has been approved for clinical use.
The metabolic framework also explains why treating co-occurring medical conditions improves autism symptoms. Conditions like gastrointestinal problems, sleep disorders, and immune dysfunction all compete for the same limited metabolic resources needed for optimal development. Treating these conditions returns energy and metabolic resources to the child for better developmental outcomes.
Naviaux emphasises that autism is “pluricausal”—it results from the integration of many subclinical stressors rather than any single factor working alone.
This explains why hundreds of different genetic and environmental factors can each increase risk, yet produce similar core symptoms. They all converge on cellular metabolism and energy signalling as a final common pathway.
The model reframes autism not as an inevitable outcome of genetics or environment alone, but as a metabolic syndrome where intervention may remain possible even after symptoms appear.
By understanding metabolism as a central factor in both brain development and autism risk, researchers and clinicians gain new tools for prevention, early detection, and treatment. – Study Finds
In A Nutshell
What they found: Scientists at University of California (San Diego) identified cellular metabolism and energy signalling as a central factor connecting all known genetic and environmental autism risk factors.
The 3-hit model: Autism develops when three factors align: inherited metabolic hypersensitivity, environmental triggers during critical developmental windows (late first trimester through 18-36 months), and persistent or repeated cellular stress activation across that early period.
Why it matters: The authors estimate that 40-50% of autism cases might be preventable through early screening and intervention, similar to how phenylketonuria (PKU) is now successfully managed.
This is a model-based projection requiring validation through clinical trials. Several screening methods can identify at-risk infants before symptoms appear.
The key player: A molecule called extracellular ATP (eATP) acts as a danger signal. When cells become hypersensitive to this signal during early development, they redirect energy away from typical brain development and toward cellular defence, altering how neural connections form.
What’s next: Researchers are developing medications called antipurinergics that target the ATP signalling pathway. Animal studies and one small human trial show promise, though larger trials are needed and no treatment is currently approved. Metabolic screening programs for pregnant women and newborns are also being developed.
Bottom line: Autism isn’t an inevitable outcome of genetics or environment alone; it’s a metabolic syndrome where the timing and persistence of cellular stress during critical developmental windows determines whether symptoms develop.
