Molecular Biophysics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal 462066, India.
ACS Chem Neurosci. 2021 Oct 6;12(19):3497-3515. doi: 10.1021/acschemneuro.1c00429. Epub 2021 Sep 9.
Voltage-dependent anion channels (VDACs) of the outer mitochondrial membrane are known conventionally as metabolite flux proteins. However, research findings in the past decade have revealed the multifaceted regulatory roles of VDACs, from governing cellular physiology and mitochondria-mediated apoptosis to directly regulating debilitating cancers and neurodegenerative diseases. VDACs achieve these diverse functions by establishing isoform-dependent stereospecific interactomes in the cell with the cytosolic constituents and endoplasmic reticulum complexes, and the machinery of the mitochondrial compartments. VDACs are now increasingly recognized as regulatory hubs of the cell. Not surprisingly, even the transient misregulation of VDACs results directly in mitochondrial dysfunction. Additionally, human VDACs are now implicated in interaction with aggregation-prone cytosolic proteins, including Aβ, tau, and α-synuclein, contributing directly to the onset of Alzheimer's and Parkinson's diseases. Deducing the interaction dynamics and mechanisms can lead to VDAC-targeted peptide-based therapeutics that can alleviate neurodegenerative states. This review succinctly presents the latest findings of the VDAC interactome, and the mode(s) of VDAC-dependent regulation of biochemical physiology. We also discuss the relevance of VDACs in pathophysiological states and aggregation-associated diseases and address how VDACs will facilitate the development of next-generation precision medicines.
电压依赖性阴离子通道（VDACs）位于线粒体外膜，传统上被认为是代谢物通量蛋白。然而，过去十年的研究发现，VDACs 具有多方面的调节作用，从调节细胞生理和线粒体介导的细胞凋亡，到直接调节恶性肿瘤和神经退行性疾病。VDACs 通过与细胞质成分和内质网复合物以及线粒体区室的机器建立依赖于异构体的立体特异性互作组，从而实现这些多样化的功能。VDACs 现在越来越被认为是细胞的调节中心。毫不奇怪，即使 VDACs 的短暂失调也会直接导致线粒体功能障碍。此外，人类 VDACs 现在与易聚集的细胞质蛋白（包括 Aβ、tau 和 α-突触核蛋白）相互作用，直接导致阿尔茨海默病和帕金森病的发生。推断相互作用的动态和机制可以导致基于 VDAC 靶向肽的治疗方法，从而减轻神经退行性状态。本综述简洁地介绍了 VDAC 互作组的最新发现，以及 VDAC 依赖的生化生理学调节模式。我们还讨论了 VDACs 在病理生理状态和聚集相关疾病中的相关性，并探讨了 VDACs 将如何促进下一代精准医疗的发展。
