The Role of Placental MFF-Mediated Mitochondrial Fission in Gestational Diabetes Mellitus.

Introduction: Gestational diabetes mellitus (GDM) refers to hyperglycemia first recognized during pregnancy, characterized by decreased insulin sensitivity and impaired glucose metabolism. Dynamic fusion and fission processes within mitochondria play critical roles in maintaining glucose metabolism homeostasis. Given the fundamental role of mitochondrial fission factor (MFF) in mitochondrial fission, the intention of this study was to investigate mitochondrial dynamics in the placentae of GDM patients and explore the role of MFF in the etiopathogenesis and progression of GDM through the modulation of glucose metabolism and insulin resistance. Methods: 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. Results: 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. Discussion: 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.