Lemasters John J
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S31-7. doi: 10.1111/j.1440-1746.2006.04643.x.
The mitochondrial inner and outer membranes have contrasting permeability characteristics. The outer membrane is non-specifically permeable to all low-molecular-weight solutes, whereas the inner membrane is impermeable except through specific transporters. After stresses and sometimes in normal physiology, the permeability of the two membranes can reverse. In the inner membrane, permeability transition pores open to cause the mitochondrial permeability transition (MPT). As the MPT involves more and more mitochondria, autophagy, apoptosis and necrosis progressively develop linked to the proportion of mitochondria injured and the extent of adenosine triphosphate (ATP) depletion, a phenomenon of necrapoptosis. By contrast, the outer membrane may decrease its permeability after certain stresses via closure of voltage-dependent anion channels (VDAC). The VDAC closure globally suppresses mitochondrial function to prevent futile ATP hydrolysis in hypoxia-ischemia and possibly the release of toxic superoxide under conditions of oxidative stress. The VDAC closure may also facilitate selective oxidation of acetaldehyde after ethanol exposure and promote aerobic glycolysis in cancer cells. By contrast, VDAC opening is proposed to stimulate oxidative phosphorylation and promote insulin release by glucose-stimulated pancreatic beta cells. Thus, VDAC serves as a global regulator, or governator, of mitochondrial function. Understanding of how these mitochondrial membrane permeability changes are themselves regulated remains incomplete and requires future study.
线粒体内膜和外膜具有截然不同的通透性特征。外膜对所有低分子量溶质具有非特异性通透性，而内膜除了通过特定转运蛋白外是不可渗透的。在应激后，有时在正常生理状态下，两层膜的通透性会发生逆转。在内膜中，通透性转换孔打开会导致线粒体通透性转换（MPT）。随着MPT涉及越来越多的线粒体，自噬、凋亡和坏死会逐渐发展，这与受损线粒体的比例以及三磷酸腺苷（ATP）耗竭的程度相关，即坏死性凋亡现象。相比之下，外膜在某些应激后可能通过关闭电压依赖性阴离子通道（VDAC）来降低其通透性。VDAC的关闭会全面抑制线粒体功能，以防止在缺氧缺血时ATP的无效水解，并可能在氧化应激条件下抑制有毒超氧化物的释放。VDAC的关闭还可能促进乙醇暴露后乙醛的选择性氧化，并促进癌细胞中的有氧糖酵解。相比之下，有人提出VDAC的开放会刺激氧化磷酸化，并促进葡萄糖刺激的胰腺β细胞释放胰岛素。因此，VDAC作为线粒体功能的全局调节因子或管理者。对这些线粒体膜通透性变化本身如何被调节的理解仍不完整，需要未来进一步研究。
