Budzinska Adrianna, Jarmuszkiewicz Wieslawa
Laboratory of Mitochondrial Biochemistry, Department of Bioenergetics, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Collegium Biologicum, Uniwersytetu Poznanskiego 6, 61-614 Poznan, Poland.
Pharmaceuticals (Basel). 2025 Jul 11;18(7):1029. doi: 10.3390/ph18071029.
Nitrogen-containing bisphosphonates (N-BPs) are commonly used drugs in the treatment of bone diseases due to their potent inhibition of the mevalonate pathway, leading to disrupted protein prenylation and reduced osteoclast activity. Although N-BPs are effective in reducing bone resorption, increasing evidence indicates their side effects on various non-skeletal cells. The aim of this review is to synthesize the current knowledge on the cellular and molecular effects of N-BPs outside the skeletal system, with particular emphasis on their impact on mitochondrial function and energy metabolism. At the cellular level, N-BPs may reduce viability, modulate inflammatory responses, trigger apoptosis, disrupt cytoskeletal organization, and influence signaling and energy metabolism. N-BPs may also impair the prenylation of proteins essential for mitochondrial dynamics and quality control, and may disrupt Ca homeostasis. As we have shown in endothelial cells, by inhibiting the mevalonate pathway, N-BPs may lead to a reduction in key components of the mitochondrial respiratory chain, such as coenzyme Q (CoQ) and -heme. These effects can contribute to impaired mitochondrial respiratory function, increased oxidative stress, and mitochondria-dependent apoptosis, affecting cellular energy metabolism and viability. These findings underscore the multifaceted impact of N-BPs beyond bone, emphasizing the importance of mitochondrial health and energy metabolism in understanding their broader biological effects and potential adverse outcomes.
含氮双膦酸盐（N-BPs）是治疗骨疾病的常用药物，因为它们能有效抑制甲羟戊酸途径，导致蛋白质异戊二烯化受阻，破骨细胞活性降低。尽管N-BPs在减少骨吸收方面有效，但越来越多的证据表明它们对各种非骨骼细胞有副作用。本综述的目的是综合目前关于N-BPs在骨骼系统外的细胞和分子效应的知识，特别强调它们对线粒体功能和能量代谢的影响。在细胞水平上，N-BPs可能降低细胞活力、调节炎症反应、引发细胞凋亡、破坏细胞骨架组织，并影响信号传导和能量代谢。N-BPs还可能损害线粒体动力学和质量控制所必需的蛋白质的异戊二烯化，并可能破坏钙稳态。正如我们在内皮细胞中所显示的，通过抑制甲羟戊酸途径，N-BPs可能导致线粒体呼吸链的关键成分减少，如辅酶Q（CoQ）和血红素。这些效应可导致线粒体呼吸功能受损、氧化应激增加和线粒体依赖性细胞凋亡，影响细胞能量代谢和活力。这些发现强调了N-BPs在骨骼之外的多方面影响，突出了线粒体健康和能量代谢在理解其更广泛的生物学效应和潜在不良后果方面的重要性。
