FUNDC1-Associated Regulation of Mitochondrial Function Is Crucial for Preventing Endothelial Injury in Hyperglycemia.

Mitochondria are intracellular organelles that regulate cell survival and death. Hyperglycemia modulates the functioning of the mitochondria in endothelial cells. We discovered that high-glucose (HG) treatment reduces FUN14 domain-containing 1 (FUNDC1) expression in endothelial cells. FUNDC1 expression in the mitochondria inhibits the proteasomal degradation of cytochrome C oxidase IV (COX-IV) and regulates mitochondrial complex I and IV activities as well as ATP synthesis under normal conditions. The FUNDC1 depletion in HG contexts affects mitochondrial complex I and IV activity as well as ATP synthesis and promotes mitochondrial damage through the loss of mitochondrial membrane potential and the production of reactive oxygen species (ROS). BAM15 is a mitochondrial uncoupler that increases mitochondrial function and endothelial survival. Cotreatment with HG and BAM15 increased the FUNDC1 protein expression level and the mitochondrial translocation of FUNDC1 in HG-treated cells. The BAM15-induced upregulation of FUNDC1 expression increased the mitochondrial expression of COX-IV, complex I and IV activity, and ATP synthesis. Our findings suggest that FUNDC1 expression in endothelial cells under hyperglycemic stress plays a crucial role in limiting vascular damage and apoptotic cell death. We discovered a mechanism through which BAM15 protects endothelial cells through FUNDC1-mediated mitophagy and metabolic regulation. Targeting FUNDC1 via mitochondrial uncoupling is a promising therapeutic strategy for treating diabetic vascular diseases.