<br>内质网-线粒体界面，Ca2+ 和细胞死亡相遇的地方,Cell Calcium

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内质网-线粒体界面，Ca2+ 和细胞死亡相遇的地方
Cell Calcium ( IF 4.3 ) Pub Date : 2023-04-25 , DOI: 10.1016/j.ceca.2023.102743
Ian de Ridder ₁ , Martijn Kerkhofs ₁ , Fernanda O Lemos ₁ , Jens Loncke ₁ , Geert Bultynck ₁ , Jan B Parys ₁

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内质网（ER）-线粒体接触位点对于钙离子在它们之间的流动至关重要，并且大量蛋白质参与将两个细胞器束缚在一起。肌醇 1,4,5-三磷酸受体 (IPR) 在此类接触位点发挥着关键作用，参与 ER 线粒体束缚，并作为 Ca 转运系统将 Ca 从 ER 输送到线粒体。在 ER-线粒体接触位点，IPR 作为多蛋白复合物发挥作用，通过伴侣葡萄糖调节蛋白 75 (GRP75) 与线粒体外膜中的电压依赖性阴离子通道 1 (VDAC1) 连接。这种 IPR-GRP75-VDAC1 复合物支持 Ca 从 ER 有效转移到线粒体膜间隙，Ca 离子可以从该间隙通过线粒体钙单向转运蛋白到达线粒体基质。在生理条件下，基础 Ca 振荡将 Ca 输送到线粒体基质，从而刺激线粒体氧化代谢。然而，当线粒体Ca超载时，[Ca]的增加会诱导线粒体通透性转换孔打开，从而引发细胞死亡。 IPR-GRP75-VDAC1 复合物形成了几种其他蛋白质的中心，这些蛋白质稳定复合物和/或调节复合物将 Ca 引导至线粒体的能力。本综述讨论了这些蛋白质及其作用机制，特别关注它们在病理状况中的作用以及对治疗策略的潜在影响。

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The ER-mitochondria interface, where Ca2+ and cell death meet

Endoplasmic reticulum (ER)-mitochondria contact sites are crucial to allow Ca flux between them and a plethora of proteins participate in tethering both organelles together. Inositol 1,4,5-trisphosphate receptors (IPRs) play a pivotal role at such contact sites, participating in both ER-mitochondria tethering and as Ca-transport system that delivers Ca from the ER towards mitochondria. At the ER-mitochondria contact sites, the IPRs function as a multi-protein complex linked to the voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane, via the chaperone glucose-regulated protein 75 (GRP75). This IPR-GRP75-VDAC1 complex supports the efficient transfer of Ca from the ER into the mitochondrial intermembrane space, from which the Ca ions can reach the mitochondrial matrix through the mitochondrial calcium uniporter. Under physiological conditions, basal Ca oscillations deliver Ca to the mitochondrial matrix, thereby stimulating mitochondrial oxidative metabolism. However, when mitochondrial Ca overload occurs, the increase in [Ca] will induce the opening of the mitochondrial permeability transition pore, thereby provoking cell death. The IPR-GRP75-VDAC1 complex forms a hub for several other proteins that stabilize the complex and/or regulate the complex's ability to channel Ca into the mitochondria. These proteins and their mechanisms of action are discussed in the present review with special attention for their role in pathological conditions and potential implication for therapeutic strategies.

更新日期：2023-04-25

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