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

Xinliang Fu^1,#, Wen Du^1,#, Tao Li², Yifei Shen¹, Ngai-Fung Ruan¹, Huiling Ling¹, Xingbo Wu¹, Ziqi Qin¹, Xiting Zhu¹, Xueqi Gan^1,*
1 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, China
2 Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China
* Corresponding Author: Xueqi Gan. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: MitoROS: Exploring Mitochondria and Oxidative Stress)

BIOCELL https://doi.org/10.32604/biocell.2026.077349

Received 08 December 2025; Accepted 09 April 2026; Published online 27 April 2026

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Abstract

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 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. 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.