Oxidative Damage Induced Disruption of Mitochondrial Quality Control Underlying Abnormal Energy Metabolism in Peripheral Leukocytes of Schizophrenia Patients

Abstract

Abstract Background and Hypothesis Mitochondrial dysfunction is increasingly implicated in schizophrenia (SZ) pathogenesis. To maintain mitochondrial homeostasis under cellular stress, a sophisticated mitochondrial quality control (MQC) mechanism has developed, encompassing mitochondrial biogenesis, dynamics, and mitophagy. Study Design This study systematically evaluated MQC in peripheral leukocytes of 42 SZ patients and 43 healthy controls through morphological analysis, MQC gene expressions, mitochondrial DNA (mtDNA) maintenance, and oxidative damage. Besides, we validated the regulatory effects of oxidative stress on MQC in vitro using a neuronal model treated with hydrogen peroxide. Study Results We observed mitochondrial fragmentation in SZ, characterized by increased organelle numbers with reduced sizes. This was supported by imbalanced MQC, with expression of biogenesis-related genes SIRT1 and TFAM upregulated (P = .008 and 0.027, respectively), and mitophagy receptor gene PHB2 suppressed (P = .041), indicating enhanced biogenesis but impaired mitophagy. Despite enhanced biogenesis, mtDNA copy number was lower (P < .001) with more oxidative damage (P = .037). Furthermore, we discovered deficits in antioxidant capacity, including reduced coenzyme Q10 levels and superoxide dismutase (SOD) activity, with SOD decline correlating with mtDNA depletion. This suggests redox imbalance contributes to MQC dysregulation, supported by findings from an oxidation-damaged neuronal model. Moreover, disrupted MQC functionally impaired energy metabolism, reflected by downregulated NDUFV1 expression (P = .031) and increased lactate-to-pyruvate ratios (P < .001). Conclusions Our findings demonstrated MQC imbalance in SZ, manifested as mitochondrial fragmentation and mtDNA depletion, probably resulted from oxidative damage. These disruptions may underlie the energy metabolism abnormalities in SZ.