Authors

D Krivska¹; T Stenzel¹; E Sokolov¹; F Winkelmann¹; E C Reisinger¹; M Sombetzki¹;  ¹ University Medical Center Rostock, Germany

Discussion

Background: Hepatic fibrosis and granuloma formation, as a consequence of tissue entrapped eggs, characterize the pathology of Schistosoma mansoni (S.m.) infection. S.m. infection affects mitochondrial membrane potential, gene expression of mitochondrial biogenesis, mitochondrial dynamics (fusion/fission), and extrinsic and intrinsic apoptosis pathways. Besides regulation of cellular homeostasis, energy production, and oxidative stress, mitochondria are also crucial players in the regulation of innate and adaptive immune responses. We have previously shown that 24-nor-ursodeoxycholic acid (norUDCA) has pronounced anti-inflammatory and anti-fibrotic effects in S.m. induced liver injury. However, the mechanism behind this effect has not been fully elucidated yet.
Therefore, we aimed to test the hypothesis if norUDCA exerts beneficial effects on hepatic fibrosis in murine schistosomiasis via balancing of mitochondrial dysfunction.
Methods: Adult NMRI mice were infected with 50 S.m. cercariae and after 12 weeks received either norUDCA- or ursodeoxycholic acid (UDCA)-enriched diet (0.5% wt/wt) in further 4 weeks for an evaluation of the effect of these bile acids on the dynamics of liver tissue mitochondria on gene expression level and respiration of isolated hepatocyte mitochondria using high-resolution respirometry.

Results: The treatment with mainly norUDCA improves mitochondrial dynamics by reducing mitochondrial fragmentation and enhancing mitochondrial inner and outer membrane fusion. Moreover, our findings display decreased O₂ consumption in all measured states of the respiratory chain, indicating a pronounced mitochondrial dysfunction caused by S.m. infection. Nevertheless, norUDCA treatment of infected animals exerts a significant advantageous effect on OXPHOS capacity and the ratio of respiration in the uncoupled state and additionally increases the electron transport system capacity and cytochrome C oxidase function.

Conclusion: Our results demonstrate that norUDCA positively affects hepatocyte mitochondria function, which in turn contributes another piece to the puzzle of the broad effects of norUDCA on S.m. associated liver pathology.