Lemasters John J, Holmuhamedov Ekhson L, Czerny Christoph, Zhong Zhi, Maldonado Eduardo N
Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC 29425, USA.
Biochim Biophys Acta. 2012 Jun;1818(6):1536-44. doi: 10.1016/j.bbamem.2011.11.034. Epub 2011 Dec 7.
Voltage dependent anion channels (VDAC) are highly conserved proteins that are responsible for permeability of the mitochondrial outer membrane to hydrophilic metabolites like ATP, ADP and respiratory substrates. Although previously assumed to remain open, VDAC closure is emerging as an important mechanism for regulation of global mitochondrial metabolism in apoptotic cells and also in cells that are not dying. During hepatic ethanol oxidation to acetaldehyde, VDAC closure suppresses exchange of mitochondrial metabolites, resulting in inhibition of ureagenesis. In vivo, VDAC closure after ethanol occurs coordinately with mitochondrial uncoupling. Since acetaldehyde passes through membranes independently of channels and transporters, VDAC closure and uncoupling together foster selective and more rapid oxidative metabolism of toxic acetaldehyde to nontoxic acetate by mitochondrial aldehyde dehydrogenase. In single reconstituted VDAC, tubulin decreases VDAC conductance, and in HepG2 hepatoma cells, free tubulin negatively modulates mitochondrial membrane potential, an effect enhanced by protein kinase A. Tubulin-dependent closure of VDAC in cancer cells contributes to suppression of mitochondrial metabolism and may underlie the Warburg phenomenon of aerobic glycolysis. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.
电压依赖性阴离子通道（VDAC）是高度保守的蛋白质，负责线粒体外膜对亲水性代谢物（如ATP、ADP和呼吸底物）的通透性。尽管此前认为VDAC保持开放状态，但VDAC的关闭正逐渐成为凋亡细胞以及非凋亡细胞中全局线粒体代谢调控的重要机制。在肝脏将乙醇氧化为乙醛的过程中，VDAC的关闭会抑制线粒体代谢物的交换，从而导致尿素生成受到抑制。在体内，乙醇作用后VDAC的关闭与线粒体解偶联协同发生。由于乙醛可独立于通道和转运体穿过膜，VDAC的关闭和解偶联共同促进线粒体醛脱氢酶将有毒的乙醛选择性地、更快速地氧化为无毒的乙酸。在单个重组VDAC中，微管蛋白会降低VDAC的电导率，而在HepG2肝癌细胞中，游离微管蛋白会负向调节线粒体膜电位，蛋白激酶A可增强这种作用。癌细胞中微管蛋白依赖性的VDAC关闭有助于抑制线粒体代谢，可能是有氧糖酵解的瓦氏效应的基础。本文是名为“VDAC的结构、功能及线粒体代谢调控”的特刊的一部分。
