Rostovtseva Tatiana K, Bezrukov Sergey M
Laboratory of Physical and Structural Biology, Program in Physical Biology, NICHD, National Institutes of Health, Rockville Pike, Bethesda, MD 20892, USA.
J Bioenerg Biomembr. 2008 Jun;40(3):163-70. doi: 10.1007/s10863-008-9145-y.
It was recently asserted that the voltage-dependent anion channel (VDAC) serves as a global regulator, or governor, of mitochondrial function (Lemasters and Holmuhamedov, Biochim Biophys Acta 1762:181-190, 2006). Indeed, VDAC, positioned on the interface between mitochondria and the cytosol (Colombini, Mol Cell Biochem 256:107-115, 2004), is at the control point of mitochondria life and death. This large channel plays the role of a "switch" that defines in which direction mitochondria will go: to normal respiration or to suppression of mitochondria metabolism that leads to apoptosis and cell death. As the most abundant protein in the mitochondrial outer membrane (MOM), VDAC is known to be responsible for ATP/ADP exchange and for the fluxes of other metabolites across MOM. It controls them by switching between the open and "closed" states that are virtually impermeable to ATP and ADP. This control has dual importance: in maintaining normal mitochondria respiration and in triggering apoptosis when cytochrome c and other apoptogenic factors are released from the intermembrane space into the cytosol. Emerging evidence indicates that VDAC closure promotes apoptotic signals without direct involvement of VDAC in the permeability transition pore or hypothetical Bax-containing cytochrome c permeable pores. VDAC gating has been studied extensively for the last 30 years on reconstituted VDAC channels. In this review we focus exclusively on physiologically relevant regulators of VDAC gating such as endogenous cytosolic proteins and mitochondrial lipids. Closure of VDAC induced by such dissimilar cytosolic proteins as pro-apoptotic tBid and dimeric tubulin is compared to show that the involved mechanisms are rather distinct. While tBid mostly modulates VDAC voltage gating, tubulin blocks the channel with the efficiency of blockage controlled by voltage. We also discuss how characteristic mitochondrial lipids, phospatidylethanolamine and cardiolipin, could regulate VDAC gating. Overall, we demonstrate that VDAC gating is not just an observation made under artificial conditions of channel reconstitution but is a major mechanism of MOM permeability control.
最近有观点认为，电压依赖性阴离子通道（VDAC）是线粒体功能的全局调节因子或调控者（Lemasters和Holmuhamedov，《生物化学与生物物理学报》1762:181 - 190，2006年）。实际上，位于线粒体与胞质溶胶界面的VDAC（Colombini，《分子细胞生物化学》256:107 - 115，2004年），处于线粒体生死的控制点。这个大通道起着“开关”的作用，决定线粒体的走向：是进行正常呼吸还是抑制线粒体代谢，进而导致细胞凋亡和死亡。作为线粒体外膜（MOM）中含量最丰富的蛋白质，VDAC负责ATP/ADP交换以及其他代谢物跨MOM的通量。它通过在几乎对ATP和ADP不可渗透的开放和“关闭”状态之间切换来控制这些过程。这种控制具有双重重要性：维持线粒体正常呼吸以及当细胞色素c和其他凋亡因子从膜间隙释放到胞质溶胶中时触发细胞凋亡。新出现的证据表明，VDAC关闭促进凋亡信号，而VDAC并未直接参与通透性转换孔或假想的含Bax的细胞色素c通透孔。在过去30年里，人们对重组VDAC通道的VDAC门控进行了广泛研究。在本综述中，我们专门关注VDAC门控的生理相关调节因子，如内源性胞质蛋白和线粒体脂质。比较了由促凋亡tBid和二聚体微管蛋白等不同胞质蛋白诱导的VDAC关闭，以表明所涉及的机制相当不同。虽然tBid主要调节VDAC电压门控，但微管蛋白以受电压控制的阻断效率阻断通道。我们还讨论了特征性线粒体脂质磷脂酰乙醇胺和心磷脂如何调节VDAC门控。总体而言，我们证明VDAC门控不仅仅是在通道重组的人工条件下的一种观察结果，而是MOM通透性控制的主要机制。
