2. Academic Validation
  3. PKA-mediated Drp1 Ser637 phosphorylation modulates mitochondrial function in the placenta of gestational diabetes mellitus

PKA-mediated Drp1 Ser637 phosphorylation modulates mitochondrial function in the placenta of gestational diabetes mellitus

  • Biochem Biophys Res Commun. 2025 Nov 19:790:152919. doi: 10.1016/j.bbrc.2025.152919.
Qiming Shi 1,  Wen Sun 2,  Zihui Zhou 3,  Jiahao Zhao 4,  Zhenyu Sun 5,  Siwen Fan 6,  Xingyu Huang 7,  Hao Fu 8,  Xia Zhu 9
Affiliations

Affiliations

  • 1 Obstetrics and Gynecology Department, Xuzhou Maternal and Child Health Hospital, Xuzhou, Jiangsu Province, 221004, China. Electronic address: [email protected].
  • 2 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. Electronic address: [email protected].
  • 3 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. Electronic address: [email protected].
  • 4 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. Electronic address: [email protected].
  • 5 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. Electronic address: [email protected].
  • 6 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. Electronic address: [email protected].
  • 7 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. Electronic address: [email protected].
  • 8 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. Electronic address: [email protected].
  • 9 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. Electronic address: [email protected].
PMID: 41197405 DOI: 10.1016/j.bbrc.2025.152919
Abstract

Background: Gestational diabetes mellitus (GDM) is characterized by the onset of abnormal glucose tolerance during pregnancy, with placental mitochondrial dysfunction implicated in its pathogenesis. This study investigated the role of dynamin-related protein 1 (Drp1) and its phosphorylation at Ser637 in regulating placental mitochondrial function in GDM.

Methods: Placental tissues were collected from normal glucose tolerance (NGT) pregnancies and GDM patients. Protein levels of Drp1 and pDrp1(Ser637), along with mitochondrial function markers, were analyzed. Human placental trophoblasts were treated with a PKA Activator to examine its role in modulating Drp1 phosphorylation. Additionally, Drp1 overexpression and inhibition (via Mdivi-1) were employed to assess mitochondrial dynamics. Associations between Drp1/pDrp1(Ser637) and oral glucose tolerance test (OGTT) results were evaluated using multivariate linear regression.

Results: Compared to controls, GDM placentas exhibited significantly elevated Drp1 expression and reduced pDrp1(Ser637) levels, accompanied by impaired mitochondrial function. In trophoblasts under high-glucose conditions, PKA activation effectively restored pDrp1(Ser637) phosphorylation and alleviated Drp1-mediated mitochondrial dysfunction. Overexpression of Drp1 in normal trophoblasts induced mitochondrial abnormalities, while Mdivi-1 treatment markedly attenuated high glucose-induced Drp1 activation and improved mitochondrial homeostasis. Multivariate analysis further identified upregulated Drp1 and downregulated pDrp1(Ser637) as independent risk factors for GDM progression.

Conclusion: Our findings demonstrate that PKA-dependent phosphorylation of Drp1 at Ser637 regulates placental mitochondrial homeostasis in GDM. Targeting this pathway may offer a novel therapeutic strategy for GDM management.

Keywords

Drp1; Gestational diabetes mellitus; Mitochondrial dysfunction; Placenta; pDrp1(Ser637).

Figures
Products