Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia-Induced Vascular Injury

Abstract

The risk of diabetic cardiovascular complications is closely linked to the length of hyperglycemia exposure. Mitophagy plays a significant role in vascular endothelial injury. However, the specific mechanisms by which mitophagy contributes to endothelial injury during sustained hyperglycemia remain unclear. In diabetic ApoE^-/- mice and human umbilical vein endothelial cell (HUVEC) models, mitophagy is enhanced following short-term and long-term high-glucose exposure. Short-term high-glucose exposure promotes Parkin-mediated mitophagy and upregulates mitochondrial fission protein 1 (Fis1) expression, whereas long-term high-glucose exposure suppresses Parkin-mediated mitophagy and downregulates Fis1. With prolonged high-glucose exposure, Syntaxin 17 (STX17) translocates from the endoplasmic reticulum to the mitochondria, activating STX17-mediated mitophagy. Silencing STX17 alleviates mitochondrial degradation, decreases reactive oxygen species (ROS) levels, enhances endothelial nitric oxide synthase (eNOS) phosphorylation, and reduces apoptosis. Silencing Fis1 accelerates the switching to STX17-mediated mitophagy, worsening endothelial dysfunction, whereas Fis1 overexpression prevents this switching, reducing ROS and apoptosis and enhancing eNOS phosphorylation. In summary, these findings suggest that the switching from Parkin-mediated to STX17-mediated mitophagy drives vascular endothelial injury following long-term hyperglycemic exposure, providing valuable insights into therapeutic strategies for diabetic cardiovascular complications.

Keywords: (diabetes; Fis1; Syntaxin 17); mitophagy; vascular endothelial injury.