UNLABELLED: Treatment of cancer patients with tyrosine kinase inhibitors (TKIs) often results in hypertension, but the underlying mechanism remains unclear. This study aimed to examine the role of mitochondrial morphology and function, particularly mitochondria-associated endoplasmic reticulum membranes (MAMs), in sunitinib-induced hypertension. METHODS: Both in vitro and in vivo experiments performed to assesse reactive oxygen species (ROS), nitric oxide (NO), endothelium-dependent vasorelaxation, systemic blood pressure, and mitochondrial function in human umbilical vein endothelial cells (HUVECs) and C57BL/6 mouse aortic endothelial cells, under vehicle or sunitinib treatment condition. RESULTS: Sunitinib increased mitochondrial ROS accumulation, decreased oxygen consumption rate, ATP production, and mitochondrial calcium ([Ca CONCLUSION: Sunitinib induces mitochondrial dysfunction, Akt/MFN2-mediated decrease in MAMs and mitochondrial elongation, and IP