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Updated: Oct 12, 2025
Human Neural Organoids for Studying Brain Cancer and Neurodegenerative Diseases
Published on: June 28, 2019
Dopamine signaling impairs ROS modulation by mitochondrial hexokinase in human neural progenitor cells
Gabriela Assis-de-Lemos1, Jamila Monteiro1, Viviane M Oliveira-Valença2
1Laboratory of Bioenergetics and Mitochondrial Physiology, Institute of Medical Biochemistry Leopoldo de Meis, Center for Health Sciences, Federal University of Rio de Janeiro (UFRJ), Brazil.
Abstract:
Dopamine signaling has numerous roles during brain development. In addition, alterations in dopamine signaling may be also involved in the pathophysiology of psychiatric disorders. Neurodevelopment is modulated in multiple steps by reactive oxygen species (ROS), byproducts of oxidative metabolism that are signaling factors involved in proliferation, differentiation, and migration. Hexokinase (HK), when associated with the mitochondria (mt-HK), is a potent modulator of the generation of mitochondrial ROS in the brain. In the present study, we investigated whether dopamine could affect both the activity and redox function of mt-HK in human neural progenitor cells (NPCs). We found that dopamine signaling via D1R decreases mt-HK activity and impairs ROS modulation, which is followed by an expressive release of H2O2 and impairment in calcium handling by the mitochondria. Nevertheless, mitochondrial respiration is not affected, suggesting specificity for dopamine on mt-HK function. In neural stem cells (NSCs) derived from induced-pluripotent stem cells (iPSCs) of schizophrenia patients, mt-HK is unable to decrease mitochondrial ROS, in contrast with NSCs derived from healthy individuals. Our data point to mitochondrial hexokinase as a novel target of dopaminergic signaling, as well as a redox modulator in human neural progenitor cells, which may be relevant to the pathophysiology of neurodevelopmental disorders such as schizophrenia.
Insights
Dopamine signaling impacts brain development by altering mitochondrial hexokinase (mt-HK) activity and reactive oxygen species (ROS) levels. Dysfunctional mt-HK in schizophrenia may contribute to neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Dopamine signaling is crucial for brain development and implicated in psychiatric disorders.
- Reactive oxygen species (ROS) are key signaling molecules in neurodevelopment.
- Mitochondrial hexokinase (mt-HK) regulates mitochondrial ROS generation.
Purpose of the Study:
- To investigate dopamine's effect on mt-HK activity and redox function in human neural progenitor cells (NPCs).
- To explore the role of mt-HK in neurodevelopmental disorders, specifically schizophrenia.
Main Methods:
- Studied dopamine's impact on mt-HK activity and ROS modulation in human NPCs.
- Utilized induced-pluripotent stem cells (iPSCs) from schizophrenia patients and healthy individuals.
- Assessed mitochondrial function, including respiration and calcium handling.
Main Results:
- Dopamine signaling via D1 receptors reduced mt-HK activity and impaired ROS modulation.
- This led to increased hydrogen peroxide (H2O2) release and compromised mitochondrial calcium handling.
- mt-HK from schizophrenia patient-derived neural stem cells failed to decrease mitochondrial ROS.
Conclusions:
- Mitochondrial hexokinase is a novel target of dopaminergic signaling in human neural progenitor cells.
- mt-HK acts as a redox modulator, and its dysfunction may be relevant to schizophrenia pathophysiology.
- These findings highlight a potential link between dopamine, mt-HK, and neurodevelopmental disorders.
