Fig. 7

A model of p66Shc orchestrates autophagy via cGAS-STING signaling in trophoblast cells of GDM.Step 1, High glucose induces an upregulation of p66Shc expression and its translocation to the mitochondria, resulting in the accumulation of ROS and a reduction in MMP. This leads to activation of the mPTP, which subsequently causes the release of ROS and mtDNA into the cytoplasm. Step 2, p66Shc translocases into mitochondrial intermembrane space promotes the formation of MAMs, which serves as a membrane source for LC3 recruitment and lipidation through an ATG5 dependent mechanism. Step 3, The cytoplasmic mtDNA triggers and activation of STING, leading to the subsequent translocation of STING from the endoplasmic reticulum to the isolation membrane. LC3-positive membranes target DNA and dysfunctional mitochondrion to autophagosomes, which results in increased autophagy in trophoblast cells. Besides, this dysregulation ultimately impairs trophoblast cell function and potentially compromises placental integrity in patients with GDM