Li Jie, Gao Ming, Wang Jia-Xin, Li Hong-Yan, Wang Pin, Yuan Fang, Liu Ai-Jing, Zhang Song-Yun
Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China.
Hebei Key Laboratory of Rare Disease, Hebei Provincial Department of Science and Technology, Shijiazhuang 050000, Hebei Province, China.
World J Diabetes. 2025 Aug 15;16(8):106833. doi: 10.4239/wjd.v16.i8.106833.
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.
To use animal and cellular models, we investigated whether TRPM7 mediated mitochondrial fission by upregulation of calcineurin (CaN)/dynamin-related protein 1 (Drp1) in DCD, and whether Troxerutin improved DCD by inhibiting TRPM7-mediated mitochondrial division.
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-Drp1, 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.
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 Drp1 expression was downregulated, and mitochondrial fission was increased. By modulating (inhibiting or overexpressing) TRPM7, it was further validated that TRPM7 activates the CaN/Drp1 pathway, resulting in an increase in mitochondrial fission and neuronal cell apoptosis. Troxerutin downregulated TRPM7/CaN/Drp1, reduced mitochondrial fission, and improved DCD.
TRPM7 promotes mitochondrial fission the CaN/Drp1 pathway. Troxerutin improves mitochondrial function and reduces neuronal damage by inhibiting this pathway, suggesting TRPM7 as a potential therapeutic target for DCD.
糖尿病认知功能障碍（DCD）是糖尿病的慢性并发症之一，但其机制目前尚不清楚。研究表明，钙超载介导的线粒体分裂是DCD的重要机制。阻断钙超载并恢复钙稳态是治疗的关键步骤。瞬时受体电位M型7（TRPM7）是导致钙超载的一个新因素。我们之前的研究表明，1型糖尿病大鼠中TRPM7的基因沉默可导致认知功能显著改善，但具体机制仍不清楚。从槐花中提取的曲克芦丁是芦丁的衍生物之一，已被证明具有神经保护作用。然而，其与TRPM7的关系仍不清楚。
利用动物和细胞模型，我们研究了在DCD中TRPM7是否通过上调钙调神经磷酸酶（CaN）/动力相关蛋白1（Drp1）介导线粒体分裂，以及曲克芦丁是否通过抑制TRPM7介导的线粒体分裂来改善DCD。
在本研究中，我们使用db/db小鼠和用高浓度葡萄糖处理的海马神经元细胞系（HT22）作为研究对象。我们使用莫里斯水迷宫、新物体识别任务和筑巢试验评估认知功能。我们使用透射电子显微镜观察线粒体形态，并使用分光光度计测量线粒体能量代谢指标。我们还使用定量实时聚合酶链反应、蛋白质免疫印迹和免疫荧光检测TRPM7、CaN、p-Drp1、半胱天冬酶-3、B细胞淋巴瘤-2相关X蛋白和B细胞淋巴瘤-2的mRNA和蛋白表达。
在患有认知功能障碍的db/db糖尿病小鼠以及暴露于高浓度葡萄糖的海马神经元中，TRPM7和CaN表达上调，磷酸化Drp1表达下调，线粒体分裂增加。通过调节（抑制或过表达）TRPM7，进一步证实TRPM7激活CaN/Drp1途径，导致线粒体分裂增加和神经元细胞凋亡。曲克芦丁下调TRPM7/CaN/Drp1，减少线粒体分裂，并改善DCD。
TRPM7通过CaN/Drp1途径促进线粒体分裂。曲克芦丁通过抑制该途径改善线粒体功能并减少神经元损伤，提示TRPM7作为DCD的潜在治疗靶点。
