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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Troxerutin improves diabetic cognitive dysfunction by inhibiting mitochondrial fission mediated by transient receptor potential melastatin 7/calcineurin/dynamin-related protein 1ser637
Jie Li, Ming Gao, Jia-Xin Wang, Hong-Yan Li, Pin Wang, Fang Yuan, Ai-Jing Liu, Song-Yun Zhang
Jie Li, Ming Gao, Jia-Xin Wang, Hong-Yan Li, Pin Wang, Song-Yun Zhang, Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Jie Li, Ming Gao, Song-Yun Zhang, Hebei Key Laboratory of Rare Disease, Hebei Provincial Department of Science and Technology, Shijiazhuang 050000, Hebei Province, China
Fang Yuan, Department of Physiology, Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Ai-Jing Liu, Department of Immunology and Rheumatology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Co-first authors: Jie Li and Ming Gao.
Author contributions: Li J curated the dataset and wrote the original draft; Li J and Gao M validated the experimental results, they contributed equally to this article, they are the co-first authors of this manuscript; Gao M and Zhang SY conceived the study and designed the research framework; Gao M, Yuan F, and Zhang SY designed the protocol; Li J, Gao M, Wang JX, Wang P, Yuan F, and Liu AJ performed the experiments and collected the data; Li HY corrected the draft and designed figures and table; Yuan F supervised the research team; Zhang SY provided essential resources for this study; Zhang SY and Gao M secured research funding to support this work; and all authors agree to be accountable for all aspects of work ensuring integrity and accuracy.
Supported by the Natural Science Foundation of Hebei Province, No. H2021206187 and No. H2021206452.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Second Hospital of Hebei Medical University, approval No. 2021AE255.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and/or analyzed during the study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Song-Yun Zhang, PhD, Department of Endocrinology, The Second Hospital of Hebei Medical University, Hepingxi Road, Shijiazhuang 050000, Hebei Province, China.
zhangsongyun2014@126.com
Received: March 12, 2025
Revised: April 30, 2025
Accepted: July 7, 2025
Published online: August 15, 2025
Processing time: 156 Days and 4.3 Hours
BACKGROUND
Diabetic cognitive dysfunction (DCD) is one of the chronic complications of diabetes, but its mechanism is currently unknown. Studies have shown that mitochondrial fission mediated by calcium overload is an important mechanism of DCD. Blocking calcium overload and restoring calcium homeostasis are key steps in treatment. Transient receptor potential melastatin 7 (TRPM7) is a novel player in causing calcium overload. Our previous studies have shown that genetic silencing of TRPM7 in type 1 diabetic rats leads to significant improvements in cognitive function, but the specific mechanism remains unclear. Troxerutin, extracted from the flowers of Sophora japonica, is one of the derivatives of rutin and has been shown to have neuroprotective effects. However, its association with TRPM7 remains unclear.
AIM
To use animal and cellular models, we investigated whether TRPM7 mediated mitochondrial fission by upregulation of calcineurin (CaN)/dynamin-related protein 1 (Drp1)ser637 in DCD, and whether Troxerutin improved DCD by inhibiting TRPM7-mediated mitochondrial division.
METHODS
In this study, we used db/db mice and hippocampal neuronal cell lines (HT22) treated with high-concentration glucose as our study subjects. We evaluated cognitive function using Morris water maze, novel object recognition tasks, and Nesting tests. We observed mitochondrial morphology using transmission electron microscopy and measured mitochondrial energy metabolism indicators using a spectrophotometer. We also detected mRNA and protein expression of TRPM7, CaN, p-Drp1ser637, caspase-3, B-cell lymphoma 2 associated X protein, and B-cell lymphoma 2 using quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence.
RESULTS
In the db/db diabetic mice with cognitive dysfunction, as well as in hippocampal neurons exposed to high-concentration glucose, TRPM7 and CaN expression were upregulated, phosphorylated Drp1ser637 expression was downregulated, and mitochondrial fission was increased. By modulating (inhibiting or overexpressing) TRPM7, it was further validated that TRPM7 activates the CaN/Drp1ser637 pathway, resulting in an increase in mitochondrial fission and neuronal cell apoptosis. Troxerutin downregulated TRPM7/CaN/Drp1ser637, reduced mitochondrial fission, and improved DCD.
CONCLUSION
TRPM7 promotes mitochondrial fission via the CaN/Drp1ser637 pathway. Troxerutin improves mitochondrial function and reduces neuronal damage by inhibiting this pathway, suggesting TRPM7 as a potential therapeutic target for DCD.
Core Tip: The expression of transient receptor potential melastatin 7 (TRPM7) was increased in diabetic cognitive dysfunction (DCD) mice and hippocampal neurons treated with high-concentration glucose. TRPM7 promoted mitochondrial fission in hippocampal neurons by upregulating calcineurin (CaN)/dynamin-related protein 1 (Drp1)ser637. The TRPM7/CaN/Drp1ser637 signaling pathway played an important role in DCD. Troxerutin improved DCD by inhibiting mitochondrial fission mediated by TRPM7/CaN/Drp1ser637.
