The SIRT1/GLUT1 axis regulates glycolysis and mitochondrial homeostasis in trophoblast cells: Implications for pre-eclampsia

Background Trophoblast cells are vital for placental formation, and their dysfunction is linked to pre-eclampsia, a pregnancy-specific disorder. SIRT1, a deacetylase that modulates oxidative stress, metabolism, and apoptosis, plays a role in various pregnancy complications. This study investigates the role of the SIRT1 in trophoblast cells and its potential involvement in pre-eclampsia. Methods HTR-8/SVneo trophoblast cells were used for in vitro experiments. SIRT1 and GLUT1 were knocked down by cell transfection, and their interaction was assessed via Co-IP. Cell proliferation, apoptosis, migration, and invasion were evaluated using CCK-8, flow cytometry, and Transwell assays. Glycolytic activity and mitochondrial function were assessed by RT-qPCR, Western blotting, TMRE, and kit assay. Results Co-IP analysis confirmed the interaction between SIRT1 and GLUT1, with SIRT1 knockdown significantly reducing GLUT1 acetylation. Knockdown of SIRT1 decreased cell migration, invasion, proliferation, and mitochondrial membrane potential, while increasing apoptosis, ROS levels, DRP1, and FIS1 expression. These effects were amplified with simultaneous SIRT1 and GLUT1 knockdown. Additionally, SIRT1 knockdown reduced MFN2, Complex IV, COX-I, HK2, PGK1, PKM2, and LDHA levels, as well as ATP levels, glucose uptake, and lactate production, with further reductions observed with both SIRT1 and GLUT1 knockdown or the addition of 2-DG. Conclusion The SIRT1/GLUT1 is essential for maintaining trophoblast cell function. Its inhibition disrupts the glycolytic activity, impairs mitochondrial function, and increases apoptosis, potentially contributing to PE. The SIRT1/GLUT1 axis may represent a potential mechanistic target for further investigation in pre-eclampsia.