Research progress on the mechanism of mitochondria-associated endoplasmic reticulum membranes in diabetic kidney disease
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摘要:
糖尿病肾病（diabetic kidney disease，DKD）是糖尿病的主要微血管并发症之一，随着糖尿病患病率持续攀升，其已成为终末期肾病的重要诱因，严重威胁患者生命健康并加剧社会医疗负担。线粒体与内质网（endoplasmic reticulum，ER）的功能障碍在DKD进展中起关键作用，而线粒体内质网相关膜（mitochondria-associated endoplasmic reticulum membrane，MAM）作为二者动态交互的核心枢纽，通过调控钙稳态、脂质代谢、线粒体动力学及细胞凋亡等过程影响DKD病理进程。本文系统综述MAM在DKD发生发展中的多重分子机制，揭示其通过调节钙离子（Ca2+）平衡、葡萄糖代谢、炎症反应及自噬等途径参与肾损伤的精细调控网络，并阐明MAM功能失调如何驱动DKD向终末期肾病转化，深入探讨MAM相关生物标志物在早期诊断中的潜力，以及靶向MAM的药物干预、基因修复等创新治疗策略，为DKD的基础机制研究与临床实践衔接提供理论参考。
Abstract:Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes. With the increasing prevalence of diabetes, it has become an important cause of end-stage renal disease, which seriously threatens the life and health of patients and aggravates the medical burden of society. The dysfunction of mitochondria and endoplasmic reticulum (ER) plays a key role in the progression of DKD, and the mitochondria-associated endoplasmic reticulum membrane (MAM) is the core hub of the dynamic interaction between the two. Mitochondrial dynamics and apoptosis affect the pathological process of DKD. This article systematically reviews the multiple molecular mechanisms of MAM in the occurrence and development of DKD, reveals its involvement in the fine regulatory network of kidney injury by regulating calcium ion (Ca2+) balance, glucose metabolism, inflammatory response and autophagy, and clarifies how MAM dysfunction drives the transformation of DKD into end-stage renal disease. In addition, this article deeply explores the potential of MAM-related biomarkers in early diagnosis, as well as innovative therapeutic strategies such as drug intervention and gene repair targeting MAM, which provides theoretical references for basic mechanism research and clinical practice of DKD.
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图 1 线粒体内质网相关膜的分子组成及相关功能
MAM：线粒体内质网相关膜；MNF1：肌细胞核因子1；MNF2：肌细胞核因子2；VAPB：囊泡相关膜蛋白B；PTPIP51：蛋白酪氨酸磷酸酶相互作用蛋白51；TOM40：外膜转位酶40；FIS1：线粒体分裂蛋白1；BAP31：B细胞受体相关蛋白31；IP3R：三磷酸肌醇受体；GRP75：葡萄糖调节蛋白75；VDAC1：电压依赖性阴离子通道1；MCU：线粒体钙单向转运体；OPR5：寡肽转运蛋白5；OPR8：寡肽转运蛋白8；MITOL：线粒体泛素连接酶；MOSPD2：运动精子域包含蛋白2；GRP78：葡萄糖调节蛋白78；WASF3：WASP家族成员3；OPA1：视神经萎缩蛋白1；DRP1：动力相关蛋白1；MFF：线粒体分裂因子；DsbA-L：二硫键氧化还原酶A样蛋白；PACS2：磷酸酶和张力蛋白同源物诱导激酶2；mTORC1：哺乳动物雷帕霉素靶蛋白复合物1；PP2A：蛋白磷酸酶2A；NLRP3：NOD样受体家族含pyrin结构域蛋白3；DAMPs：损伤相关分子模式；TXNIP：硫氧还蛋白相互作用蛋白；BCL2：B细胞淋巴瘤2；CANX：钙联蛋白
表 1 线粒体内质网相关膜在糖尿病肾病中的相关早期标志物及治疗策略
功 能 分 类 作 用 早期标志物 线粒体内质网膜相关蛋白 肌醇1,4,5-三磷酸受体、电压依赖性阴离子通道等显著变化 钙稳态 钙浓度的异常变化是线粒体内质网相关膜功能失调的早期信号 脂质代谢与氧化应激 血液、尿液中脂肪酸等标志物间接反映线粒体内质网相关膜功能 治疗策略 药物干预 熊去氧胆酸：减轻内质网应激 钙通道调节剂：恢复钙稳态 抗氧化剂：减缓氧化应激 脂质代谢调节剂：改善线粒体内质网相关膜功能 基因修复 修复线粒体内质网相关膜相关蛋白基因，改善功能失调 细胞干预 激活自噬途径，清除损伤细胞器 
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