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Ca2+ handling at the mitochondria-ER contact sites in neurodegeneration
Cell Calcium ( IF 4 ) Pub Date : 2021-08-05 , DOI: 10.1016/j.ceca.2021.102453
Dmitry Lim 1 , Giulia Dematteis 1 , Laura Tapella 1 , Armando A Genazzani 1 , Tito Calì 2 , Marisa Brini 3 , Alexei Verkhratsky 4
Affiliation  

Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are morpho-functional units, formed at the loci of close apposition of the ER-forming endomembrane and outer mitochondrial membrane (OMM). These sites contribute to fundamental cellular processes including lipid biosynthesis, autophagy, apoptosis, ER-stress and calcium (Ca2+) signalling. At MERCS, Ca2+ ions are transferred from the ER directly to mitochondria through a core protein complex composed of inositol-1,4,5 trisphosphate receptor (InsP3R), voltage-gated anion channel 1 (VDAC1), mitochondrial calcium uniporter (MCU) and adaptor protein glucose-regulated protein 75 (Grp75); this complex is regulated by several associated proteins. Deregulation of ER-mitochondria Ca2+ transfer contributes to pathogenesis of neurodegenerative and other diseases. The efficacy of Ca2+ transfer between ER and mitochondria depends on the protein composition of MERCS, which controls ER-mitochondria interaction regulating, for example, the transversal distance between ER membrane and OMM and the extension of the longitudinal interface between ER and mitochondria. These parameters are altered in neurodegeneration. Here we overview the ER and mitochondrial Ca2+ homeostasis, the composition of ER-mitochondrial Ca2+ transfer machinery and alterations of the ER-mitochondria Ca2+ transfer in three major neurodegenerative diseases: motor neurone diseases, Parkinson disease and Alzheimer's disease.



中文翻译:

神经退行性变中线粒体-ER 接触位点的 Ca2+ 处理

线粒体-内质网 (ER) 接触位点 (MERCS) 是形态功能单位,形成于 ER 形成内膜和线粒体外膜 (OMM) 紧密并置的位点。这些位点有助于基本的细胞过程,包括脂质生物合成、自噬、细胞凋亡、ER 应激和钙 (Ca 2+ ) 信号传导。在 MERCS,Ca 2+离子通过由肌醇 1,4,5 三磷酸受体 (InsP 3 R)、电压门控阴离子通道 1 (VDAC1)、线粒体钙单向转运体组成的核心蛋白复合物从 ER 直接转移到线粒体(MCU) 和衔接蛋白葡萄糖调节蛋白 75 (Grp75);这种复合物受几种相关蛋白的调节。ER-线粒体Ca 2+的失调转移有助于神经退行性疾病和其他疾病的发病机制。ER和线粒体之间Ca 2+转移的功效取决于MERCS的蛋白质组成,它控制ER-线粒体相互作用,例如ER膜和OMM之间的横向距离以及ER和线粒体之间纵向界面的延伸。这些参数在神经退行性变中发生了改变。在这里,我们概述了三种主要神经退行性疾病:运动神经元疾病、帕金森病和阿尔茨海默病中的 ER 和线粒体 Ca 2+稳态、ER-线粒体 Ca 2+转移机制的组成和 ER-线粒体 Ca 2+ 转移的改变

更新日期:2021-08-13
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