Dopamine Signaling Impairs ROS Modulation by Mitochondrial Hexokinase and leads to H2O2 release from Human Neural Progenitor Cells
Dopamine signaling has numerous roles during brain development. In addition, alterations in dopamine 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 which 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 this 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. Accordingly, dopamine-exposed NPCs showed a significant decrease in the protein content of HKI. Nevertheless, mitochondrial respiration is not affected, suggesting specificity for dopamine on mt-HK function. In neural stem cells (NSCs) derived from iPSCs of schizophrenic patients, mt-HK is unable to modulate mitochondrial ROS, in contrast to 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.
Steps to reproduce
Some of the protocols used are explained in detail in the reference cited bellow [Assis-de-Lemos et al. A Protocol to Study Mitochondrial Function in Human Neural Progenitors and iPSC‐Derived Astrocytes, 2020].