Orrenius Sten
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden.
Toxicol Lett. 2004 Apr 1;149(1-3):19-23. doi: 10.1016/j.toxlet.2003.12.017.
Although it has long been known that impairment of mitochondrial function may lead to ATP depletion and necrotic cell death, recent work has revealed that these organelles also play an important role in the regulation of apoptotic cell death by mechanisms which have been conserved through evolution. Thus, it seems that a number of toxicants target the mitochondria and promote their release of cytochrome c and other pro-apoptotic proteins, which can trigger caspase activation and other parts of the apoptotic process. Cytochrome c release is governed by the Bcl-2 family of proteins, whereas subsequent caspase activation is modulated by other proteins, including inhibitor of apoptosis proteins (IAPs) and heat shock proteins. Recent findings indicate that cytochrome c extrusion occurs by a two-step process, which is initiated by a disruption of the association of the hemoprotein with cardiolipin, the phospholipid that anchors it to the outer surface of the inner mitochondrial membrane. Release of the solubilized pool of cytochrome c into the cytosol may then occur by permeabilization of the outer mitochondrial membrane mediated by pro-apoptotic Bcl-2 family proteins, notably Bax and Bak, or by Ca2+-triggered mitochondrial permeability transition. Taken together, these findings have placed the mitochondria in the focus of apoptosis research and further underlined the important function of these organelles in cell life and death.
尽管长期以来人们都知道线粒体功能受损可能导致ATP耗竭和坏死性细胞死亡，但最近的研究表明，这些细胞器在通过进化保守机制调节凋亡性细胞死亡中也起着重要作用。因此，似乎许多毒物靶向线粒体并促进其释放细胞色素c和其他促凋亡蛋白，这可触发半胱天冬酶激活及凋亡过程的其他部分。细胞色素c的释放受Bcl-2家族蛋白调控，而随后的半胱天冬酶激活则由其他蛋白调节，包括凋亡抑制蛋白（IAPs）和热休克蛋白。最近的研究结果表明，细胞色素c的外排是一个两步过程，首先是血红素蛋白与心磷脂（将其锚定在内线粒体膜外表面的磷脂）的结合被破坏。然后，溶解的细胞色素c池可能通过促凋亡Bcl-2家族蛋白（特别是Bax和Bak）介导的线粒体外膜通透性增加，或通过Ca2+触发的线粒体通透性转换释放到细胞质中。综上所述，这些发现使线粒体成为凋亡研究的焦点，并进一步强调了这些细胞器在细胞生死中的重要功能。
