CypD-mediated mitochondrial dysfunction contributes to titanium ion-induced MC3T3-E1 cell injury

• Published in: Biochemical and biophysical research communications 2023-02, Vol.644, p.15-24
• Main Authors: Mao, Yixin, Chen, Yang, Cai, Wenjin, Jiang, Wanying, Sun, Xiaoyu, Zeng, Jun, Wang, Hongning, Wang, Xia, Dong, Wenmei, Ma, Jianfeng, Jaspers, Richard T., Huang, Shengbin, Wu, Gang
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cyclophilin D; Cyclophilins - metabolism; Cyclosporine - pharmacology; Mice; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial reactive oxygen species; Osteoblasts; Oxidative Stress; Peptidyl-Prolyl Isomerase F - metabolism; Titanium - pharmacology; Titanium ion
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.12.088

Titanium (Ti) ion can stimulate osteoblast apoptosis and therefore have a high potential to play a negative role in the aseptic loosening of implants. Mitochondrial abnormalities are closely related to osteoblast dysfunction. However, the mitochondrial molecular mechanism of Ti ion induced osteoblastic cell apoptosis is still unclear. This study investigated in vitro mitochondrial oxidative stress (mtROS) mediated mitochondrial dysfunction involved in Ti ion-induced apoptosis of murine MC3T3-E1 osteoblastic cells. In addition to reducing mitochondrial membrane potential (MMP) and decreasing adenosine triglyceride production, exposure to Ti ions increased mitochondrial oxidative stress. Moreover, mitochondrial abnormalities significantly contributed to Ti ion induction of osteoblastic cellular apoptosis. A mitochondria-specific antioxidant, mitoquinone (MitoQ), alleviated Ti ion-induced mitochondrial dysfunction and apoptosis in osteoblastic cells, indicating that Ti ion mainly induces mitochondrial oxidative stress to produce a cytotoxic effect on osteoblasts. Here we show that the primary regulator of mitochondrial permeability transition pore (mPTP), cyclophilin D (CypD), is involved in mitochondrial dysfunction and osteoblast cell apoptosis induced by Ti ion. Overexpression of CypD exacerbates osteoblast apoptosis and impairs osteogenic function. Moreover, detrimental effects of CypD were rescued by cyclosporin A (CsA), an inhibitor of CypD, which shows its protective effect on mitochondrial and osteogenic osteoblast functions. Based on new insights into the mitochondrial mechanisms underlying Ti ion-induced apoptosis of osteoblastic cells, the findings of this study lay the foundation for the clinical use of CypD inhibitors to prevent or treat implant failure. [Display omitted] •Titanium ion induces cell apoptosis and inhibits osteogenic function in osteoblasts.•Titanium ion causes mitochondrial dysfunction and increases mtROS production.•Titanium ion upregulates CypD expression that triggers mPTP opening.