Neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and Rett syndrome, represent complex conditions characterized by high clinical and biological heterogeneity. In recent years, a growing body of evidence has identified mitochondrial dysfunction as a shared pathogenic mechanism, capable of contributing to the development and progression of these disorders. In particular, alterations in mitochondrial dynamics (fusion and fission), mitophagy, and redox control systems seem to converge in a state of chronic oxidative stress and neuronal bioenergetic impairment. This review discusses the role of mitochondria in key processes of neuronal development, analyzes the main experimental and clinical evidence in NDD, and explores the potential translational implications of mitochondria-centered therapeutic approaches in the context of precision medicine.
Introduction
Neurodevelopmental disorders comprise a heterogeneous group of early-onset conditions, characterized by persistent alterations in cognitive, behavioral, and social functions. According to the DSM-5, they include, among others, ASD, ADHD, intellectual disability, and communication disorders. Despite phenotypic differences, these conditions show significant overlap in terms of genetic vulnerability, developmental trajectories, and neuropsychiatric comorbidities.
Traditionally, research on NDD has focused on synaptic and neurotransmitter alterations. However, a more integrated view of pathophysiology suggests that neuronal energy metabolism and mitochondrial quality control represent central nodes in the regulation of brain development. In this context, mitochondrial dysfunction emerges as a transversal pathogenic axis, capable of influencing neurogenesis, neuronal migration, synaptogenesis, and plasticity.
Mitochondria and energy requirements of the developing brain
The human brain, while representing about 2% of total body weight, consumes up to 20% of the energy produced by the body. During embryonic and postnatal development, this energy requirement is further increased, making neurons particularly vulnerable to perturbations in mitochondrial function.
Mitochondria are not mere ATP generators, but multifunctional organelles involved in the regulation of calcium homeostasis, controlled production of reactive oxygen species (ROS), biosynthesis of intermediate metabolites, and modulation of gene expression through redox-dependent signals. These functions are essential in the various stages of neuronal development, from the proliferation of neural stem cells to the maturation of synapses.
Mitochondrial dynamics: fusion and fission
Mitochondria are highly dynamic organelles, subject to continuous processes of fusion and fission that regulate their morphology, intracellular distribution, and functionality. Mitochondrial fusion allows for the dilution of damage and maintenance of bioenergetic efficiency, while fission is fundamental for the segregation of damaged mitochondria and adaptation to local energy demands.
In neurodevelopmental disorders, dysregulation of this balance leads to the accumulation of dysfunctional mitochondria, resulting in reduced ATP production and increased oxidative stress. In particular, mutations in genes involved in mitochondrial fusion have been identified in subgroups of individuals with ASD, suggesting a direct link between structural alterations of mitochondria and neurodevelopmental dysfunctions.
Mitophagy and mitochondrial quality control
Mitophagy represents the main mechanism of mitochondrial quality control, through which damaged mitochondria are selectively recognized and degraded. The PINK1/Parkin pathway plays a crucial role in this process, promoting the ubiquitination of mitochondrial proteins and the subsequent formation of autophagosomes.
Experimental evidence indicates that in animal models of Rett syndrome, mitophagy is significantly impaired, resulting in the accumulation of defective mitochondria and increased neuronal vulnerability to oxidative stress. These observations strengthen the hypothesis that altered mitochondrial clearance substantially contributes to the pathogenesis of NDD.
Role of mitochondria in key processes of neuronal development
During the proliferation of neural stem cells, mitochondria provide the energy necessary for DNA replication and cell division. Insufficient ATP production can lead to a reduction in the stem cell pool and premature or aberrant differentiation.
During neuronal migration, mitochondria redistribute toward the anterior regions of the cell, supporting ATP-dependent cytoskeletal processes. Alterations in mitochondrial function can result in delayed or disorganized migration, leading to abnormal cortical layering.
Finally, during synaptogenesis and synaptic plasticity, mitochondria located in presynaptic terminals and dendritic spines regulate neurotransmitter release, calcium buffering, and antioxidant defense. Deficits in these processes have been associated with reduced dendritic complexity, alterations in synaptic density, and impairment of cognitive functions.
Clinical evidence of mitochondrial dysfunction in NDD
Clinical and translational studies have documented, in subjects with ASD, elevated levels of oxidative stress markers and the presence of mitochondrial DNA deletions, indicative of compromised mitochondrial function. In ADHD as well, associations between mitochondrial dysfunction, oxidative stress, and cognitive deficits have been described.
Cellular models derived from induced pluripotent stem cells (iPSC) of patients with Rett syndrome show altered mitochondrial dynamics and greater susceptibility to oxidative damage, providing important confirmation of the role of mitochondrial homeostasis in human pathology.
Therapeutic implications and precision medicine perspectives
The growing understanding of the role of mitochondria in NDD opens new therapeutic perspectives. Interventions aimed at restoring the fusion-fission balance, enhancing mitophagy, or modulating mitochondrial permeability could reduce the accumulation of defective mitochondria and limit oxidative damage.
Moreover, the upregulation of the coactivator PGC-1α, a key regulator of mitochondrial biogenesis, represents a promising strategy to improve neuronal bioenergetic capacity. The identification of early biomarkers of mitochondrial dysfunction could finally enable a precision medicine approach, tailoring therapeutic interventions to individual biological profiles and integrating them with nutritional, antioxidant, and behavioral strategies.
Conclusions
Taken together, current evidence indicates mitochondrial homeostasis as a unifying pathogenic axis in the pathophysiology of neurodevelopmental disorders. Alterations in mitochondrial dynamics and autophagic clearance converge on oxidative stress and synaptic dysfunction, substantially contributing to the clinical manifestations of NDD. The clinical validation of mitochondria-centered therapeutic approaches represents a priority for future research and could pave the way for innovative regenerative strategies, significantly improving the quality of life of people affected by these conditions.
Yang Z., Luo Y., Yang Z., et al.
Mitochondrial dynamics dysfunction and neurodevelopmental disorders: From pathological mechanisms to clinical translation.
Neural Regeneration Research. 2025;21(5):1926-1946.
DOI: 10.4103/NRR.NRR-D-24-01422