Our study demonstrates that MFF-mediated mitochondrial fission inhibits insulin sensitivity and upregulates glucose transport in GDM, which is related to offspring exposure to a hyperglycemic intrauterine environment. These results provide a novel therapeutic target for addressing GDM that may mitigate unfavorable pregnancy outcomes.

40 Placental tissues were obtained from pregnant women undergoing cesarean section with GDM (n=20) and those with normoglycemia (n=20). To mimic the intrauterine high glucose environment, immortalized human-derived first-trimester extravillous trophoblast cells HTR8/SVneo were used and treated in a high glucose environment. Immunofluorescence was utilized to analyze MFF expression in placental tissues and mitochondrial length in HTR8/SVneo cells. The expression levels of glucose transporters (GLUTs) and other pivotal proteins involved in mitochondrial dynamics and the insulin signaling pathway, were assessed by Western blotting. Additionally, cellular glucose uptake capacity was determined using a glucose assay kit.

MFF expression was greater in the GDM group than in the normoglycemic group. In a high-glucose environment, the expression of fusion-related proteins OPA1, MFN1 and MFN2 decreased while the expression of DRP1 and MFF increased, indicating that the mitochondrial dynamics of trophoblast cells shift toward fission. Elevated mitochondrial fission hinders the insulin signaling pathway, resulting in a reduction in glucose uptake by HTR8/SVneo cells and a concurrent decrease in GLUT4 expression.