Recent Reports on Redox Stress-Induced Mitochondrial DNA Variations, Neuroglial Interactions, and NMDA Receptor System in Pathophysiology of Schizophrenia

Schizophrenia (SZ) is a chronic psychiatric disorder affecting several people worldwide. Mitochondrial DNA (mtDNA) variations could invoke changes in the OXPHOS system, calcium buffering, and ROS production, which have significant implications for glial cell survival during SZ. Oxidative stress has been implicated in glial cells-mediated pathogenesis of SZ; the brain comparatively more prone to oxidative damage through NMDAR. A confluence of scientific evidence points to mtDNA alterations, Nrf2 signaling, dynamic alterations in dorsolateral prefrontal cortex (DLPFC), and provocation of oxidative stress that enhance pathophysiology of SZ. Furthermore, the alterations in excitatory signaling related to NMDAR signaling were particularly reported for SZ pathophysiology. Current review reported the recent evidence for the role of mtDNA variations and oxidative stress in relation to pathophysiology of SZ, NMDAR hypofunction, and glutathione deficiency. NMDAR system is influenced by redox dysregulation in oxidative stress, inflammation, and antioxidant mediators. Several studies have demonstrated the relationship of these variables on severity of pathophysiology in SZ. An extensive literature search was conducted using Medline, PubMed, PsycINFO, CINAHL PLUS, BIOSIS Preview, Google scholar, and Cochrane databases. We summarize consistent evidence pointing out a plausible model that may elucidate the crosstalk between mtDNA alterations in glial cells and redox dysregulation during oxidative stress and the perturbation of NMDA neurotransmitter system during current therapeutic modalities for the SZ treatment. This review can be beneficial for the development of promising novel diagnostics, and therapeutic modalities by ascertaining the mtDNA variations, redox state, and efficacy of pharmacological agents to mitigate redox dysregulation and augment NMDAR function to treat cognitive and behavioral symptoms in SZ.

Automated summary

This article summarizes the role of mitochondrial DNA (mtDNA) variations and oxidative stress in the pathophysiology of schizophrenia (SZ). It highlights the perturbation of the NMDA neurotransmitter system and the interaction between mtDNA alterations in glial cells and redox dysregulation during oxidative stress in SZ treatment.