Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation

This work demonstrates the effects of a newly synthesized conjugate of the plant triterpenoid betulin and the penetrating cation F16 used for mitochondrial targeting. The resulting F16-betulin conjugate revealed a mitochondria-targeted effect, decreasing the mitochondrial potential and inducing superoxide overproduction in rat thymocytes in vitro. It has been suggested that this may cause the cytotoxic effect of the conjugate, which significantly exceeds the effectiveness of its precursors, betulin and F16. Using isolated rat liver mitochondria, we found that the F16-betulin conjugate has a surface-active effect on mitochondrial membranes, causing organelle aggregation. This effect of the derivative resulted in a dose-dependent decrease in mitochondrial transmembrane potential, as well as suppression of respiration and oxidative phosphorylation, especially in the case of nicotinamide adenine dinucleotide (NAD)-fueled organelles. In addition, the F16-betulin conjugate caused an increase in H2O2 generation by mitochondria fueled with glutamate and malate. These effects of the derivative can presumably be due to the powerful suppression of the redox activity of complex I of the mitochondrial electron transport chain. The paper discusses how the mitochondria-targeted effects of the F16-betulin conjugate may be related to its cytotoxic effects.

Automated summary

This study demonstrates the targeted effects of a newly synthesized F16-betulin conjugate on mitochondria and its cytotoxicity. The conjugate reduces mitochondrial potential, induces superoxide overproduction, and surface-active aggregation of mitochondria. It also suppresses respiration, oxidative phosphorylation, and increases H2O2 generation, possibly through inhibition of complex I of the mitochondrial electron transport chain.