Clozapine blunts mitochondrial biogenesis in differentiating adipocytes: The increased ATP demand is met via stimulation of electron transport chain expression and activity in residual mitochondria

Abstract

Clozapine (CLZ), a second-generation antipsychotic, is associated with an elevated risk of metabolic syndrome, the underlying mechanism of which remains poorly understood. We recently showed that CLZ inhibits lipid accumulation and CAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ expression in early differentiating SW872 liposarcoma cells. Additionally, while not affecting viability, CLZ disrupts the cellular redox state of these cells by inhibiting NADPH oxidase-dependent ROS formation, thereby leading to nuclear factor (erythroid-derived2)-like 2 downregulation, reduced antioxidant defence and increased mitochondrial ROS emission.

We confirmed and extended these results by showing that, under the same conditions, CLZ reduces the size of the lipid droplets, inhibits the otherwise increased expression of transcription factors regulating mitochondrial biogenesis, as peroxisome proliferator-activated receptor γ coactivator 1-α, and prevents the increase in mitochondrial DNA and mass. Consistently, decreased expression of mitochondrial proteins as thioredoxin 2, 2-oxoglutarate/malate carrier, and translocase of outer mitochondrial membrane 20 was also observed. However, the expression of various components of the electron transport chain was unexpectedly increased, and this event was accompanied by enhanced mitochondrial dehydrogenase activity, coupled oxygen consumption, mitochondrial membrane potential, ATP synthesis and ROS production. Moreover, residual mitochondria appeared remarkably enlarged and functional, with dense and organized cristae and uniform electron density.

Thus, early adipocytes differentiated with or without CLZ meet the increased ATP demand by switching from glycolysis to oxidative phosphorylation, respectively via enhanced mitochondrial biogenesis, and increased activity of residual mitochondria.