Autism: When The Body's Defense System Interferes With Brain Development

Autism can arise when a natural bodily defense mechanism, called the cellular danger response, remains activated for too long during brain development. This response normally protects the organism, but when it occurs in excess, especially in genetically predisposed children exposed to adverse environmental factors, it can interfere with normal brain formation. This model helps integrate genetics, environment, and metabolism and suggests that, in some cases, autism can be prevented or its symptoms reduced with early interventions.

Autism spectrum disorder is a neurodevelopmental condition that affects how a person perceives the world, communicates, and interacts socially. It usually manifests in the first years of life and may involve difficulties in social communication, repetitive patterns of behavior, and sensory alterations, such as hypersensitivity to sounds, lights, or touch.

It is estimated that autism affects millions of people worldwide, with a wide variability of manifestations, which explains the use of the term "spectrum." For more than a century, researchers have been trying to understand its biological causes. Throughout this time, numerous genetic and environmental factors associated with increased risk have been identified, but for a long time an integrated explanation connecting these factors into a single coherent model was lacking.

Recent advances in studies that simultaneously analyze multiple levels of biology, such as genes, metabolism, and cellular function, have allowed the identification of a possible common denominator for the development of autism. This denominator is a fundamental biological mechanism called the cellular response to danger.

This is an evolutionarily ancient response, present in all living beings, whose main function is to protect the organism from threats such as infections, inflammation, toxins, physical trauma, or intense stress. Under normal conditions, this response is temporary and beneficial, helping the body to recover and restore balance. The problem arises when it is activated at the wrong time in development or remains activated for a prolonged period.

The cellular response to danger functions as a metabolic alarm system for the organism. When a cell perceives a threat, it changes its internal functioning to prioritize survival. These changes begin in the mitochondria, structures responsible for energy production within cells.

Mitochondria adjust their activity, altering how energy is produced and used. This directly affects cellular metabolism, that is, the set of chemical reactions that keep the cell alive and functional. Since the brain is an organ extremely dependent on energy and precise chemical signals to develop properly, any prolonged deviation in this balance can have significant consequences for neurodevelopment.

During the activation of the cellular response to danger, cells release a molecule called extracellular adenosine triphosphate into the surrounding environment. This molecule acts as a warning signal, alerting other cells that something is wrong.

At the same time, structural and functional changes occur in the mitochondria, which begin to produce different metabolites, that is, chemical substances derived from metabolism. These metabolites function as messengers that influence various body systems, including the nervous system, the immune system, and the endocrine system.

This response is not limited to a single cell or tissue. It affects the organism as a whole, regulating channels that control the entry and exit of ions in cells, systems that transport chemical substances, the release and reuptake of neurotransmitters in the brain, and even enzymes responsible for metabolizing medications, vitamins, and environmental toxins.

Furthermore, the cellular response to danger interacts with broader stress regulation systems, such as the autonomic nervous system, which controls involuntary functions like heartbeat and digestion, and the axis that connects the brain to the glands responsible for releasing stress hormones.

Based on this knowledge, the authors propose an integrated model to explain how autism spectrum disorder can develop. According to this model, three factors need to occur together.

The first factor is a genetic predisposition; that is, the child is born with genetic variants that make their cells more sensitive to metabolic changes and danger signals. The second factor is early exposure to environmental stimuli that activate the cellular response to danger, such as infections, inflammation, maternal stress, or exposure to certain toxins during pregnancy or shortly after birth. The third factor is the persistence or repetition of these stimuli for several months during a critical period of brain development, which extends from the end of gestation to the first years of life.

When these three factors combine, the cellular response to danger can remain activated long enough to interfere with normal brain development. Instead of directing energy and metabolic resources toward the proper formation of neural connections, the organism remains in a prolonged state of defense. This can alter how brain circuits are organized, contributing to the behavioral and cognitive characteristics observed in autism.

One important aspect of this model is that it suggests autism is not caused by a single isolated factor, but by a sequence of interconnected biological events. Even in conditions with a strong genetic influence, such as certain inborn errors of metabolism, this step-by-step pattern can occur. This opens the possibility of preventive interventions.

Since environmental factors and the persistence of the cellular response to danger are potentially modifiable, identifying at-risk children before the onset of symptoms may allow for strategies that reduce or even prevent the development of the disorder.

Even when diagnosis occurs after the onset of clinical signs, this model suggests that interventions targeting metabolism and cell signaling can significantly reduce the most disabling symptoms.

READ MORE:

A 3-hit metabolic signaling model for the core symptoms of autism spectrum disorder

Robert K. Naviaux 

Mitochondrion. Volume 87, March 2026, 102096

https://doi.org/10.1016/j.mito.2025.102096

Abstract:

A 3-hit metabolic signaling model of the causes of autism spectrum disorder (ASD) is described. The 3-hits required for ASD are: 1) inheritance of a genotype that sensitizes mitochondria and/or eATP-stimulated, intracellular calcium signaling to environmental change, 2) early exposure to environmental triggers that activate the metabolic features of the cell danger response (CDR), and 3) recurrent or persistent exposure to CDR-activating triggers for at least 3–6 months during the critical neurodevelopmental window from the late 1st trimester of pregnancy to the first 18–36 months of life. The three hits associated with an increased risk of ASD can be functionally classified as primers, triggers, and amplifiers of the CDR, respectively. Since the CDR is maintained by metabolic signaling, this new model creates a unified intellectual framework for understanding how the diverse features of ASD are connected. The example of phenylketonuria (PKU) is given to show that even disorders with very strong genetic predispositions can follow this 3-hit developmental paradigm and still be treatable using the principles of metabolic signaling. Since the 2nd and 3rd hits are modifiable, this model predicts that if the children at greatest risk can be diagnosed and treated before symptoms occur, some of these children may never develop ASD, and if diagnosed after symptoms occur, the core symptoms that are most disabling can be decreased significantly.