Mitochondrial Calcium Uniporter(MCU)Inhibition Disrupts Bone Remodeling and Impairs Mitochondrial Function via Aberrant Mitochondrial DynamicsOA
Objectives: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.Methods: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 in vivo model to explore the role of MCU in bone structure phenotype through bone microstructural analysis and histological examination.Results: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 thatμCT 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.Conclusion: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.
Xinliang Fu;Wen Du;Tao Li;Yifei Shen;Ngai-Fung Ruan;Huiling Ling;Xingbo Wu;Ziqi Qin;Xiting Zhu;Xueqi Gan
State Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaDepartment of Anesthesiology,Laboratory of Mitochondrial Metabolism and Perioperative Medicine,National Clinical Research Center for Geriatrics,West China Hospital of Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu,ChinaState Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu,China
医药卫生
Mitochondrial calcium uniporter(MCU)mitochondrial dynamicsmitochondrial functionsbone remodelingosteogenic function
《BIOCELL》 2026 (7)
P.208-229,22
supported by the National Natural Science Foundation of China (82370935,81870802)Sichuan Province Science and Technology Support Program Grant (2023YFS0244)Sichuan Science andTechnology Program (2025ZNSFSC0768)Clinical Research Project Funded by West China Hospital of StomatologySichuan University (LCYJ-MS-202302)The Key Research and Development Support Program of the Chengdu Scienceand Technology Bureau (2024-YF05-00505-SN)and Research Project on Graduate Education and Teaching Reform ofSichuan University (GSSCU2024105).
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