Perturbation in Mitochondrial Network Dynamics and in Complex I Dependent Cellular Respiration in Schizophrenia

• Published in: Biological psychiatry (1969) Vol. 69; no. 10; pp. 980 - 988
• Main Authors: Rosenfeld, Marina, Brenner-Lavie, Hanit, Ari, Shunit Gal-Ben, Kavushansky, Alexandra, Ben-Shachar, Dorit
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.2011
• Subjects: Adult; Analysis of Variance; Animals; Antipsychotic Agents - pharmacology; Antipsychotic drugs; Benzimidazoles - metabolism; bipolar disorder; Carbocyanines - metabolism; Cell Line, Transformed; Cell Respiration - physiology; dopamine; Electron Transport Complex I - metabolism; Female; GTP Phosphohydrolases - metabolism; Herpesvirus 4, Human - genetics; Humans; Lymphocytes - diagnostic imaging; Lymphocytes - physiology; Male; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; Membrane Transport Proteins - metabolism; Middle Aged; Mitochondria - drug effects; Mitochondria - physiology; Mitochondria - ultrastructure; Mitochondrial Membrane Transport Proteins; mitochondrial network dynamics; Mitochondrial Proteins - metabolism; mitochondrial respiration; Oxygen Consumption - physiology; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Prefrontal Cortex - ultrastructure; Psychiatry; Rats; Rats, Sprague-Dawley; schizophrenia; Schizophrenia - drug therapy; Schizophrenia - pathology; Ultrasonography; Young Adult; mitochondrial network dynamics; bipolar disorder; Antipsychotic drugs; schizophrenia; dopamine; mitochondrial respiration
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2011.01.010

Mitochondria have been suggested to be involved in the pathology of bipolar disorder (BD) and schizophrenia. However, the mechanism underlying mitochondrial dysfunction is unclear. Mitochondrial network dynamics, which reflects cellular metabolic state, is important for embryonic development, synapse formation, and neurodegeneration. This study aimed to investigate mitochondrial network dynamics and its plausible association with abnormal cellular oxygen consumption in schizophrenia. Viable Epstein-Barr virus (EBV)-transformed lymphocytes (lymphoblastoids) from DSM-IV diagnosed patients with schizophrenia ( n = 17), BD ( n = 15), and healthy control subjects ( n = 15) were assessed for mitochondrial respiration, mitochondrial dynamics, and relevant protein levels by oxygraph, confocal microscopy, and immunoblotting, respectively. Respiration of schizophrenia-derived lymphoblastoids was significantly lower compared with control subjects, and was twice as sensitive to dopamine (DA)-induced inhibition. Unlike DA, haloperidol inhibited complex I–driven respiration to a similar extent in both schizophrenia and the control cells. Both drugs interact with complex I but at different sites. At the site of DA interaction, we found alterations in protein levels of three subunits of complex I in schizophrenia. In addition, we observed structural and connectivity perturbations in the mitochondrial network, associated with alterations in the profusion protein OPA1, which was similarly reduced in schizophrenia prefrontal cortex specimens. None of these alterations were observed in the BD cells, which were similar to control cells. We show impaired mitochondrial network dynamics associated with reduced cellular respiration and complex I abnormalities in schizophrenia but not in BD. If these findings represent disease-specific alterations, they may become an endophenotype biomarker for schizophrenia.