TY  - EJOU
AU  - Fu, Xinliang 
AU  - Du, Wen 
AU  - Li, Tao 
AU  - Shen, Yifei 
AU  - Ruan, Ngai-Fung 
AU  - Ling, Huiling 
AU  - Wu, Xingbo 
AU  - Qin, Ziqi 
AU  - Zhu, Xiting 
AU  - Gan, Xueqi 

TI  - Mitochondrial Calcium Uniporter (MCU) Inhibition Disrupts Bone Remodeling and Impairs Mitochondrial Function via Aberrant Mitochondrial Dynamics
T2  - BIOCELL

PY  - 
VL  - 
IS  - 
SN  - 1667-5746

AB  - <b>Objectives:</b> Mitochondrial function is intricately linked to osteogenic and osteoclastic differentiation. The mitochondrial calcium uniporter (MCU) is a critical regulator of mitochondrial function, influencing key aspects of cellular metabolism and signaling. However, the precise mechanisms by which MCU modulates osteogenic activity remain unclear. This study aimed to elucidate the impact of MCU-mediated regulation of mitochondrial function on bone remodeling and to explore the underlying mechanisms. <b>Methods:</b> The mouse pre-osteoblastic cells (MC3T3-E1) were treated with the MCU-specific inhibitor Ru265 during osteogenic induction to assess changes in osteogenic differentiation capacity, mitochondrial function, and mitochondrial dynamics. Additionally, MCU global knockout (MCU KO) mice were employed as an <i>in vivo</i> model to explore the role of MCU in bone structure phenotype through bone microstructural analysis and histological examination. <b>Results:</b> Quantitative reverse transcription (qRT) PCR, western blotting, alizarin Red-S (ARS) staining, and alkaline phosphatase (ALP) activity analyses revealed that the inhibition of MCU function by Ru265 downregulates ALP activity (about 59.60% of the control group) and the expression of osteogenic markers in MC3T3-E1 cells. Dramatically increased dynamin-related protein 1 (Drp1) expression (about 1.13 times of the control group), decreased mitofusion-2 (Mfn2) expression (about 14.51% of the control group), and reduced mitochondrial membrane potential (MMP) (about 55.16% of the control group) were observed, all indicating substantial disruption of mitochondrial dynamics and function in MC3T3-E1 cells. The corroborating evidence is that μCT and histological analyses of MCU global knockout mice revealed impaired osteogenic differentiation, reduced bone mass formation, and deteriorated trabecular bone microstructure compared with wild-type mice. <b>Conclusion:</b> MCU inhibition elicits aberrant mitochondrial dynamics and mitochondrial dysfunction, thereby impairing osteogenic function and disrupting bone remodeling, which could have promising implications for bone metabolism.
KW  - Mitochondrial calcium uniporter (MCU); mitochondrial dynamics; mitochondrial functions; bone remodeling; osteogenic function

DO  - 10.32604/biocell.2026.077349