Hellebrand E E, Varbiro G
Institute of Science and Technology in Medicine, School of Pharmacy, Keele University, UK.
Drug Discov Ther. 2010 Apr;4(2):54-61.
Apoptosis is a genetically conserved mechanism that eliminates unnecessary or surplus cells and is also involved in the pathomechanism of a wide variety of diseases. The intrinsic pathway of apoptosis includes the mitochondria where numerous pro-apoptotic proteins are sequestered and their release marks the point-of-no-return, indicating the ultimate commitment to cell death. The mitochondrial permeability transition (mPT) is a mechanism enabling the release of Cytochrome-c (Cyt-c), AIF and other pro-apoptotic proteins, and is characterized by an alteration in the permeability of the organelle's membrane. This is due to reactive oxygen species or Ca(2+) triggered dynamic assemble of a trans bi-membrane channel from various protein components including the voltage dependent anion channel, the adenine nucleotide translocase, the cyclophyllin D that enables solutes up to 1.5 kDa to pass through. The resultant influx of water into the mitochondrial matrix leads to mitochondrial swelling and the rupture of the membranes. Numerous agents can inhibit mPT including amiodarone, a widely used antiarrhythmic agent. Modification of this benzofuran derivate with nitroxides or their secondary amine derivates that exhibits antioxidant properties leads to the enhancement of mPT inhibitory effect of the original compound. Furthermore this hybrid compound is also capable of influencing the necrotic cell death pathway. This strategy may prove to be beneficial to increase the effectiveness of other mPT inhibitory agents. However, further studies are necessary to identify the components and structure of the permeability transition pore in order to design more effective mPT inhibitory compounds to fully exploit the therapeutic potential of this novel drug target.
细胞凋亡是一种基因保守机制，可清除不必要或多余的细胞，并且也参与多种疾病的发病机制。细胞凋亡的内在途径包括线粒体，众多促凋亡蛋白被隔离于其中，它们的释放标志着细胞凋亡不可逆转的临界点，表明细胞最终走向死亡。线粒体通透性转换（mPT）是一种能使细胞色素c（Cyt-c）、凋亡诱导因子（AIF）及其他促凋亡蛋白释放的机制，其特征是细胞器膜通透性发生改变。这是由于活性氧或Ca(2+)触发了由包括电压依赖性阴离子通道、腺嘌呤核苷酸转位酶、亲环蛋白D等多种蛋白质成分组成的跨双膜通道的动态组装，使得分子量达1.5 kDa的溶质能够通过。由此导致的水流入线粒体基质会引起线粒体肿胀和膜破裂。许多药物可抑制mPT，包括广泛使用的抗心律失常药物胺碘酮。用具有抗氧化特性的氮氧化物或其仲胺衍生物对这种苯并呋喃衍生物进行修饰，可增强原化合物对mPT的抑制作用。此外，这种杂合化合物还能够影响坏死性细胞死亡途径。这一策略可能被证明有助于提高其他mPT抑制剂的有效性。然而，有必要进一步研究以确定通透性转换孔的组成和结构，从而设计出更有效的mPT抑制化合物，以充分挖掘这一新型药物靶点的治疗潜力。
