Clozapine suppresses NADPH oxidase activation, counteracts cytosolic H2O2, and triggers early onset mitochondrial dysfunction during adipogenesis of human liposarcoma SW872 cells

• Published in: Redox biology 2023-11, Vol.67, p.102915-102915, Article 102915
• Main Authors: Blandino, Giulia, Fiorani, Mara, Canonico, Barbara, De Matteis, Rita, Guidarelli, Andrea, Montanari, Mariele, Buffi, Gloria, Coppo, Lucia, Arnér, Elias S.J., Cantoni, Orazio
• Format: Article
• Language: English
• Subjects: Adipocyte differentiation; Clozapine; Medicin och hälsovetenskap; Mitochondrial dysfunction; Mitochondrial ROS; NADPH oxidase; Research Paper
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2023.102915

Long-term treatment of schizophrenia with clozapine (CLZ), an atypical antipsychotic drug, is associated with an increased incidence of metabolic disorders mediated by poorly understood mechanisms. We herein report that CLZ, while slowing down the morphological changes and lipid accumulation occurring during SW872 cell adipogenesis, also causes an early (day 3) inhibition of the expression/nuclear translocation of CAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ. Under the same conditions, CLZ blunts NADPH oxidase-derived reactive oxygen species (ROS) by a dual mechanism involving enzyme inhibition and ROS scavenging. These effects were accompanied by hampered activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2)-dependent antioxidant responses compared to controls, and by an aggravated formation of mitochondrial superoxide. CLZ failed to exert ROS scavenging activities in the mitochondrial compartment but appeared to actively scavenge cytosolic H2O2 derived from mitochondrial superoxide. The early formation of mitochondrial ROS promoted by CLZ was also associated with signs of mitochondrial dysfunction. Some of the above findings were recapitulated using mouse embryonic fibroblasts. We conclude that the NADPH oxidase inhibitory and cytosolic ROS scavenging activities of CLZ slow down SW872 cell adipogenesis and suppress their Nrf2 activation, an event apparently connected with increased mitochondrial ROS formation, which is associated with insulin resistance and metabolic syndrome. Thus, the cellular events characterised herein may help to shed light on the more detailed molecular mechanisms explaining some of the adverse metabolic effects of CLZ. [Display omitted] •CLZ inhibits NOX-2 activity and scavenges cytosolic (but not mitochondrial) ROS.•CLZ blunts early NOX-2-dependent ROS formation in differentiating adipocytes.•CLZ blunts Nrf2 activation and the ensuing antioxidant response.•CLZ slows down adipogenesis.•CLZ anticipates mitochondrial ROS formation and causes mitochondrial dysfunction.