Laboratory of Mitochondrial Biochemistry, Department of Bioenergetics, Adam Mickiewicz University, Collegium Biologicum, Uniwersytetu Poznanskiego 6, 61-614, Poznan, Poland.
Sci Rep. 2023 Sep 27;13(1):16205. doi: 10.1038/s41598-023-43377-3.
Nitrogen-containing bisphosphonates (NBPs), compounds that are widely used in the treatment of bone disorders, may cause side effects related to endothelial dysfunction. The aim of our study was to investigate the effects of chronic 6-day exposure to two common bone-preserving drugs, alendronate and zoledronate, on endothelial function and oxidative metabolism of cultured human endothelial cells (EA.hy926). NBPs reduced cell viability, induced oxidative stress and a pro-inflammatory state and downregulated the prenylation-dependent ERK1/2 signaling pathway in endothelial cells. In addition, NBPs induced increased anaerobic respiration and slightly increased oxidative mitochondrial capacity, affecting mitochondrial turnover through reduced mitochondrial fission. Moreover, by blocking the mevalonate pathway, NBPs caused a significant decrease in the level of coenzyme Q10, thereby depriving endothelial cells of an important antioxidant and mitochondrial electron carrier. This resulted in increased formation of reactive oxygen species (ROS), upregulation of antioxidant enzymes, and impairment of mitochondrial respiratory function. A general decrease in mitochondrial respiration occurred with stronger reducing fuels (pyruvate and glutamate) in NBP-treated intact endothelial cells, and significantly reduced phosphorylating respiration was observed during the oxidation of succinate and especially malate in NBP-treated permeabilized endothelial cells. The observed changes in oxidative metabolism caused a decrease in ATP levels and an increase in oxygen levels in NBP-treated cells. Thus, NBPs modulate the energy metabolism of endothelial cells, leading to alterations in the cellular energy state, coenzyme Q10 redox balance, mitochondrial respiratory function, and mitochondrial turnover.
含氮双膦酸盐（NBPs）是广泛用于治疗骨骼疾病的化合物，可能会引起与内皮功能障碍相关的副作用。我们的研究目的是研究慢性 6 天暴露于两种常见的骨保护药物，阿仑膦酸钠和唑来膦酸，对培养的人内皮细胞（EA.hy926）的内皮功能和氧化代谢的影响。NBPs 降低细胞活力，诱导氧化应激和促炎状态，并下调内皮细胞中依赖异戊烯基化的 ERK1/2 信号通路。此外，NBPs 诱导增加无氧呼吸，并略微增加氧化线粒体容量，通过减少线粒体分裂来影响线粒体周转率。此外，通过阻断甲羟戊酸途径，NBPs 导致辅酶 Q10 的水平显著降低，从而剥夺内皮细胞重要的抗氧化剂和线粒体电子载体。这导致活性氧（ROS）的形成增加、抗氧化酶的上调以及线粒体呼吸功能的损害。在完整的内皮细胞中，用 NBP 处理的细胞中一般的线粒体呼吸减少，并且在用 NBP 处理的通透性内皮细胞中，在氧化琥珀酸和特别是苹果酸时，观察到磷酸化呼吸显著减少。氧化代谢的观察到的变化导致 ATP 水平降低和 NBP 处理细胞中氧水平增加。因此，NBPs 调节内皮细胞的能量代谢，导致细胞能量状态、辅酶 Q10 氧化还原平衡、线粒体呼吸功能和线粒体周转率的改变。
