Caterino Marianna, Ruoppolo Margherita, Mandola Annalisa, Costanzo Michele, Orrù Stefania, Imperlini Esther
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.
Mol Biosyst. 2017 Nov 21;13(12):2466-2476. doi: 10.1039/c7mb00434f.
Voltage-dependent anion channels (VDACs) are a family of three mitochondrial porins and the most abundant integral membrane proteins of the mitochondrial outer membrane (MOM). VDACs are known to be involved in metabolite/ion transport across the MOM and in many cellular processes ranging from mitochondria-mediated apoptosis to the control of energy metabolism, by interacting with cytosolic, mitochondrial and cytoskeletal proteins and other membrane channels. Despite redundancy and compensatory mechanisms among VDAC isoforms, they display not only different channel properties and protein expression levels, but also distinct protein partners. Here, we review the known protein interactions for each VDAC isoform in order to shed light on their peculiar roles in physiological and pathological conditions. As proteins associated with the MOM, VDAC opening/closure as a metabolic checkpoint is regulated by protein-protein interactions, and is of pharmacological interest in pathological conditions such as cancer. The interactions involving VDAC1 have been characterized more in depth than those involving VDAC2 and VDAC3. Nevertheless, the so far explored VDAC-protein interactions for each isoform show that VDAC1 is mainly involved in the maintenance of cellular homeostasis and in pro-apoptotic processes, whereas VDAC2 displays an anti-apoptotic role. Despite there being limited information on VDAC3, this isoform could contribute to mitochondrial protein quality control and act as a marker of oxidative status. In pathological conditions, namely neurodegenerative and cardiovascular diseases, both VDAC1 and VDAC2 establish abnormal interactions aimed to counteract the mitochondrial dysfunction which contributes to end-organ damage.
电压依赖性阴离子通道（VDACs）是由三个线粒体孔蛋白组成的家族，是线粒体外膜（MOM）中含量最丰富的整合膜蛋白。已知VDACs通过与胞质、线粒体和细胞骨架蛋白以及其他膜通道相互作用，参与代谢物/离子跨线粒体外膜的转运以及从线粒体介导的细胞凋亡到能量代谢控制等许多细胞过程。尽管VDAC亚型之间存在冗余和补偿机制，但它们不仅表现出不同的通道特性和蛋白质表达水平，而且具有不同的蛋白质伴侣。在这里，我们综述了每种VDAC亚型已知的蛋白质相互作用，以阐明它们在生理和病理条件下的特殊作用。作为与线粒体外膜相关的蛋白质，VDAC的开放/关闭作为一个代谢检查点，受蛋白质-蛋白质相互作用的调节，在癌症等病理条件下具有药理学意义。与VDAC1相关的相互作用比与VDAC2和VDAC3相关的相互作用得到了更深入的研究。然而，迄今为止对每种亚型所探索的VDAC-蛋白质相互作用表明，VDAC1主要参与细胞稳态的维持和促凋亡过程，而VDAC2具有抗凋亡作用。尽管关于VDAC3的信息有限，但该亚型可能有助于线粒体蛋白质质量控制，并作为氧化状态的标志物。在病理条件下，即神经退行性疾病和心血管疾病中，VDAC1和VDAC2都会建立异常相互作用，以对抗导致终末器官损伤的线粒体功能障碍。
