The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance.
The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance.
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线粒体相关内质网膜诱导胰岛素抵抗的分子机制
DOI：
10.3389/fendo.2020.592129
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发表时间：
2020
影响因子：
5.2
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Cheng H;Gang X;He G;Liu Y;Wang Y;Zhao X;Wang G
线粒体和内质网 (ER) 通过线粒体相关 ER 膜 (MAM) 在多个位点连接。已知这些关联在维持细胞稳态中发挥重要作用。 MAM 信号传导受损对许多疾病产生广泛影响，例如肥胖、糖尿病和神经退行性疾病。越来越多的证据表明，MAM 通过不同的途径影响胰岛素信号传导，包括与 Ca2+ 信号传导、脂质代谢、线粒体功能、内质网应激反应和炎症相关的途径。 MAM 信号传导改变是不同组织（包括肝脏、肌肉，甚至大脑）胰岛素抵抗的一个共同特征。在肝脏中，MAM 是关键的葡萄糖感应调节剂，并被认为是胰岛素信号传导的枢纽。据报道，MAM 完整性受损会扰乱肝脏对营养转变期间葡萄糖可用性变化的反应，并诱导肝脏胰岛素抵抗。同时，这些效应可以通过加强 MAM 相互作用来挽救。相反，一些研究提出，增强的内质网-线粒体连接不利于肝脏胰岛素信号传导，并可能导致线粒体功能障碍。因此，考虑到这些相互矛盾的结果，MAM 在肝脏胰岛素信号传导调节中所发挥的作用仍然难以捉摸。同样，在骨骼肌中，增强的 MAM 形成可能对糖尿病早期有益，而持续的 MAM 增强会加剧胰岛素抵抗。此外，最近的研究表明，ER 应激可能是 MAM 诱导大脑胰岛素抵抗的主要途径，尤其是在下丘脑。本综述将讨论 MAM 相关胰岛素抵抗的可能机制，以及针对 MAM 治疗 2 型糖尿病的治疗潜力。
Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.