["The Journal of Physiology, Volume 604, Issue 11, Page 4186-4207, 1 June 2026. ", "\nAbstract figure legend Calciprotein particles (CPPs) are small calcium‐ and phosphate‐containing nanoaggregates associated with the development of vascular disease (CVD) in chronic kidney disease (CKD). Previously, we have shown that CPPs induce endothelial cell (EC) dysfunction, possibly contributing to CVD in CKD, but the underlying molecular mechanisms remain unknown. In the current study, we demonstrate that exposure of ECs to CPPs resulted in an increase of both cytosolic and mitochondrial calcium (Ca2+) and altered mitochondrial processes including reduced mitochondrial respiration, mitochondrial membrane potential and antioxidant capacity. By using a mitochondrial permeability transition pore (mPTP) inhibitor, cyclosporin A, EC activation and cell death caused by CPPs could be attenuated. These data indicate that CPP‐induced Ca2+ overload is a key process in mitochondrial dysfunction, activation and cell death of ECs, which may contribute to CVD in CKD. Interventions targeting CPP‐induced mitochondrial dysfunction might preserve EC function and alleviate vascular dysfunction in CKD.\n\n\n\n\n\n\n\n\n\nAbstract\nCalciprotein particles (CPPs) are calcium‐ and phosphate‐containing nanoparticles numbers of which are increased in patients with chronic kidney disease (CKD). CPPs have been associated with the development of vascular disease, although the underlying mechanisms are unknown. We previously showed that CPPs induce endothelial cell (EC) dysfunction by reducing nitric oxide (NO) bioavailability and generating superoxide (O2.−). Here, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca2+) overload, which may trigger mitochondrial dysfunction and, consequently, EC activation. Exposure of human umbilical vein ECs to CPPs resulted in significantly increased cytosolic and mitochondrial Ca2+ levels compared to vehicle‐treated ECs. Proteome analysis demonstrated impaired endoplasmic reticulum calcium signalling, and decreased enrichment of proteins in the mitochondrial OXPHOS complexes I–III in CPP‐exposed ECs. Respirometry data confirmed these findings and demonstrated decreased basal and maximal respiration in CPP‐exposed ECs. This was accompanied by reduced mitochondrial membrane potential, reduced antioxidant capacity and loss of mitochondria. In the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor, CPP‐induced EC activation and cell death were attenuated. Taken together, our data indicate that CPP‐induced Ca2+ overload is an important trigger of mitochondrial dysfunction, and EC activation and cell loss, which eventually may contribute to the development of vascular diseases in CKD. Interventions that target CPP‐induced mitochondrial dysfunction might preserve EC function and possibly alleviate the development of vascular diseases in CKD.\n\n\n\n\n\n\n\n\n\nKey points\n\nCalciprotein particles (CPPs) are calcium‐ and phosphate‐containing nanoparticles numbers of which are increased in patients with chronic kidney disease and which have been associated with the development of vascular disease.\nIn this study, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca2+) overload in endothelial cells, thereby triggering mitochondrial dysfunction and endothelial activation.\nWe show that exposure of HUVECs (human umbilical vein endothelial cells) to CPPs results in increased cytosolic and mitochondrial Ca2+ levels, which is associated with alterations in mitochondrial processes (proteome analysis), cellular respiration, mitochondrial integrity and number.\nCPP‐induced EC activation and cell death were attenuated in the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor.\nOur data indicate that CPP‐induced Ca2+ overload triggers mitochondrial dysfunction, endothelial activation and cell loss. Interventions that target CPP‐induced mitochondrial dysfunction might preserve EC function in chronic kidney disease.\n\n\n"]