Authors:
Ines Khadimallah (Prilly-Lausanne | CH)
Margot Fournier (Prilly - Lausanne | CH)
Jan-Harry Cabungcal (Prilly - Lausanne | CH)
Martine Cleusix (Prilly - Lausanne | CH)
Raoul Jenni (Prilly - Lausanne | CH)
Paul Klauser (Prilly - Lausanne | CH)
Michel Cuenod (Prilly - Lausanne | CH)
Philippe Conus (Prilly - Lausanne | CH)
Kim Q. Do (Prilly - Lausanne | CH)
Aims
Mitochondria play a pivotal role in regulating cellular functions including bioenergetics, calcium homeostasis, redox signaling, and apoptotic cell death, all crucial for neuronal activity, sprouting, development and survival. Impairments in mitochondrial structure, network dynamics, electron transport system activity, transcriptome, proteome and in sequence of mitochondrial-relevant genes both in brain and in peripheral cells are implicated in schizophrenia (SZ). As oxidative stress appears as a common hub in SZ pathophysiology, it is vital to understand the interplay between mitochondrial dysfunction and redox impairment, and to clarify if redox susceptibility confers a predisposition to mitochondrial impairments in SZ patients. Here we investigated (1) oxidative stress impact on mitochondrial integrity in the redox dysregulated Gclm-KO mice (70% decrease in glutathione level and oxidative stress from juvenile stage until adulthood); (2) mitochondrial response to stress in early psychosis patients (EPP); (3) impact of redox susceptibility (GCLC high-risk genotypes) on mitochondrial markers.
Methods
Effect of oxidative stress on mitochondrial morphology: ultrastructural changes in mPFC of Gclm-KO mice characterized by electron microscopy.
Fibroblasts from EPP and healthy controls were used to assess mitochondrial characteristics (complex 1 subunit alterations, fusion/fission and pro-/anti-apoptotic markers) in basal and oxidative stress conditions.
Results
We found an increased of mitochondrial damage in Gclm-KO mice compared to wild-type mice in parallel to oxidative stress, suggesting impaired energy production and ROS generation.
Profiling of mitochondrial response to oxidative stress in EPP fibroblasts showed altered levels of mitochondrial markers. Discriminant analysis revealed that the response to oxidative stress of mitochondrial markers efficiently separate EPP from controls and individuals with different redox susceptibility (i.e. different polymorphism in GCLC gene). Mitochondria profiling in patients’ fibroblasts thus appears as a powerful approach for patients’ stratification.
Conclusion
These results indicate that mitochondrial abnormalities as observed in SZ mouse model and patients may result from a redox dysregulation. These abnormalities may enhance ROS production, impair mitochondria clearance and motility and altogether lower energy production at sites with high energetic demand (e.g. at synapses or in parvalbumin interneurons).