Kinnally Kathleen W, Antonsson Bruno
Department of Basic Sciences, New York University College of Dentistry, 345 East 24th Street, New York, NY 10010, USA.
Apoptosis. 2007 May;12(5):857-68. doi: 10.1007/s10495-007-0722-z.
The crucial step in the intrinsic, or mitochondrial, apoptotic pathway is permeabilization of the mitochondrial outer membrane. Permeabilization triggers release of apoptogenic factors, such as cytochrome c, from the mitochondrial intermembrane space into the cytosol where these factors ensure propagation of the apoptotic cascade and execution of cell death. However, the mechanism(s) underlying permeabilization of the outer membrane remain controversial. Two mechanisms, involving opening of two different mitochondrial channels, have been proposed to be responsible for the permeabilization; the permeability transition pore (PTP) in the inner membrane and the mitochondrial apoptosis-induced channel (MAC) in the outer membrane. Opening of PTP would lead to matrix swelling, subsequent rupture of the outer membrane, and an unspecific release of intermembrane proteins into the cytosol. However, many believe PTP opening is a consequence of apoptosis and this channel is thought to principally play a role in necrosis, not apoptosis. Activation of MAC is exquisitely regulated by Bcl-2 family proteins, which are the sentinels of apoptosis. MAC provides specific pores in the outer membrane for the passage of intermembrane proteins, in particular cytochrome c, to the cytosol. The electrophysiological characteristics of MAC are very similar to Bax channels and depletion of Bax significantly diminishes MAC activity, suggesting that Bax is an essential constituent of MAC in some systems. The characteristics of various mitochondrial channels and Bax are compared. The involvement of MAC and PTP activities in apoptosis of disease and their pharmacology are discussed.
内源性或线粒体凋亡途径的关键步骤是线粒体外膜的通透性改变。通透性改变会触发凋亡因子（如细胞色素c）从线粒体膜间隙释放到细胞质中，这些因子在细胞质中确保凋亡级联反应的传播和细胞死亡的执行。然而，线粒体外膜通透性改变的潜在机制仍存在争议。有两种机制，涉及打开两种不同的线粒体通道，被认为与通透性改变有关；内膜中的通透性转换孔（PTP）和外膜中的线粒体凋亡诱导通道（MAC）。PTP的开放会导致基质肿胀，随后外膜破裂，膜间隙蛋白非特异性释放到细胞质中。然而，许多人认为PTP的开放是凋亡的结果，并且这个通道主要被认为在坏死而非凋亡中起作用。MAC的激活受到Bcl-2家族蛋白的精确调控，Bcl-2家族蛋白是凋亡的哨兵。MAC在外膜上提供特定的孔道，使膜间隙蛋白，特别是细胞色素c，进入细胞质。MAC的电生理特性与Bax通道非常相似，Bax的缺失会显著降低MAC的活性，这表明在某些系统中Bax是MAC的重要组成部分。文中比较了各种线粒体通道和Bax的特性。还讨论了MAC和PTP活性在疾病凋亡中的作用及其药理学。
