Biasutto Lucia, Azzolini Michele, Szabò Ildikò, Zoratti Mario
CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy.
CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biology, Viale G. Colombo 3, 35121 Padova, Italy.
Biochim Biophys Acta. 2016 Oct;1863(10):2515-30. doi: 10.1016/j.bbamcr.2016.02.012. Epub 2016 Feb 21.
Over the past 30years the mitochondrial permeability transition - the permeabilization of the inner mitochondrial membrane due to the opening of a wide pore - has progressed from being considered a curious artifact induced in isolated mitochondria by Ca(2+) and phosphate to a key cell-death-inducing process in several major pathologies. Its relevance is by now universally acknowledged and a pharmacology targeting the phenomenon is being developed. The molecular nature of the pore remains to this day uncertain, but progress has recently been made with the identification of the FOF1 ATP synthase as the probable proteic substrate. Researchers sharing this conviction are however divided into two camps: these believing that only the ATP synthase dimers or oligomers can form the pore, presumably in the contact region between monomers, and those who consider that the ring-forming c subunits in the FO sector actually constitute the walls of the pore. The latest development is the emergence of a new candidate: Spastic Paraplegia 7 (SPG7), a mitochondrial AAA-type membrane protease which forms a 6-stave barrel. This review summarizes recent developments of research on the pathophysiological relevance and on the molecular nature of the mitochondrial permeability transition pore. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
在过去30年里，线粒体通透性转换——由于一个宽孔的开放导致线粒体内膜通透性增加——已从被认为是由钙离子和磷酸盐在分离的线粒体中诱导产生的一种奇特假象，发展成为几种主要病理学中诱导细胞死亡的关键过程。如今其相关性已得到普遍认可，并且针对该现象的药理学研究正在开展。迄今为止，该孔的分子本质仍不确定，但最近在将FOF1 ATP合酶鉴定为可能的蛋白质底物方面取得了进展。然而，持有这种观点的研究人员分为两个阵营：一方认为只有ATP合酶二聚体或寡聚体能够形成孔道，大概是在单体之间的接触区域；另一方则认为FO结构域中形成环的c亚基实际上构成了孔道的壁。最新进展是出现了一个新的候选者：痉挛性截瘫7型（SPG7）蛋白，一种形成六柱桶状结构的线粒体AAA型膜蛋白酶。本综述总结了关于线粒体通透性转换孔道病理生理相关性和分子本质的研究最新进展。本文是由皮埃尔·松沃、皮埃尔·梅克勒和让 - 克洛德·马蒂诺编辑的名为《线粒体通道》特刊的一部分。
