Article Dans Une Revue The Journal of Physiology Année : 2025

Calciprotein particle‐induced calcium overload triggers mitochondrial dysfunction in endothelial cells

Résumé

Calciprotein 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.

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hal-04993762 , version 1 (17-03-2025)

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Lian Feenstra, Laurent Chatre, Benoit Bernay, Julien Pontin, Mirjam F Mastik, et al.. Calciprotein particle‐induced calcium overload triggers mitochondrial dysfunction in endothelial cells. The Journal of Physiology, 2025, pp.1-22. ⟨10.1113/jp287656⟩. ⟨hal-04993762⟩
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