Reductive Stress and Dysregulated Energy Metabolism in Schizophrenia: Mechanisms and Therapeutic Targets

Reductive stress, defined by excessive accumulation of reducing equivalents such as NADH, disrupts cellular redox balance and is emerging as a detrimental factor in schizophrenia (SZ). It is closely related to the mitochondrial defects commonly seen in SZ, which implies its importance in impaired energy metabolism. Reductive stress intersects with oxidative stress pathways and causes an underappreciated additional burden on cellular systems. The integrated stress response (ISR) is an adaptive pathway typically activated by mitochondrial oxidative phosphorylation defects and other stressors. Emerging evidence indicates that reductive stress can independently activate the ISR. These findings highlight the crucial role of reductive stress in disease pathophysiology, although the process is not fully understood. Therefore, there is a need for innovative therapeutic approaches that can address reductive stress and mitochondrial dysfunction.