The effect of triclosan uncovers the possible involvement of complex II in the oxidation of glycerol-3-phosphate in brain mitochondria.

Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) links the oxidative phosphorylation, glycolysis, and phospholipid biosynthesis and essentially contributes to ROS production by mitochondria in certain tissues. The pattern of biological effects of mGPDH dysregulation resembles that of chronic exposure to triclosan (Tcs), an unusual complex II inhibitor. Here we propose a hypothesis that the membrane-embedded regions of mGPDH and complex II form a common ubiquinone-binding center, which would be disturbed by Tcs. In this context, we test the potential of Tcs to inhibit mGPDH-related activities (respiration and ROS production) in isolated rat brain mitochondria (RBM). In the presence of moderate concentrations of glycerol-3-phosphate (G3P) and Ca2+, RBM demonstrated a limited ability to support oxidative phosphorylation and generation of superoxide anion and H2O2 via the reversed and transmembrane electron transport (from mGPDH to the flavins of complexes I and II). Tcs suppressed G3P- and 3-hydroxybutyrate (3-HB)-supported respiration and induced high-amplitude mitochondrial swelling. Exogenous cytochrome c restored the respiration in the presence of 3-HB but not G3P. In the presence of rotenone and thenoyltrifluoroacetone, the inhibitors of complexes I and II, Tcs inhibited antimycin A-activated and G3P-supported ROS production, which was accompanied by the oxidation of cytochromes b/heme b of complexes III/II. The 3-HB-supported ROS production and the extent of the reduction of cytochromes b were not affected by Tcs directly. These data confirm our hypothesis. However, for its rigorous assessment, we propose several approaches. Confirmation of this hypothesis will be of great importance for the development of promising mGPDH-targeted anticancer drugs.