Scorrano Luca
Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
Novartis Found Symp. 2007;287:47-55; discussion 55-9. doi: 10.1002/9780470725207.ch4.
Mitochondria are complex organelles whose internal structure and cytosolic organization is controlled by a growing number of 'mitochondria-shaping' proteins. These include mitochondrial proteins such as the large dynamin-related GTPases Mitofusin (Mfn) 1 and 2, Optic Atrophy 1 (Opa1); as well as the cytosolic dynamin-related protein 1 (Drp1) and its receptor on the outer mitochondrial membrane Fis1. These proteins influence not only the shape of mitochondria, but also the function of the organelle and eventually integrated cellular signalling cascades, including apoptosis. We undertook a genetic approach to elucidate the function and regulation of these proteins. Opa1 is involved in the regulation of mitochondrial fusion, by co-operating with Mfn1. Moreover, Opa1 independently from mitochondrial fusion regulates the crista remodelling pathway of apoptosis. Oligomers of a membrane bound and a soluble form of Opa1, produced by Parl, an inner membrane rhomboid protease, are disrupted early during apoptosis, leading to remodelling of the mitochondrial cristae and redistribution of the mitochondrial cytochrome c. The importance of this pathway is substantiated by the phenotype of the Parl-/- mouse, which displays excess apoptosis in multiple tissues. Cells lacking Parl are more susceptible to apoptotic stimuli and the reintroduction of a soluble form of Opa1 rescues their phenotype.
线粒体是复杂的细胞器，其内部结构和胞质组织受越来越多的“线粒体塑形”蛋白控制。这些蛋白包括线粒体蛋白，如大型动力相关GTP酶线粒体融合蛋白（Mfn）1和2、视神经萎缩蛋白1（Opa1）；以及胞质动力相关蛋白1（Drp1）及其在线粒体外膜上的受体Fis1。这些蛋白不仅影响线粒体的形状，还影响细胞器的功能以及最终整合细胞信号级联反应，包括细胞凋亡。我们采用遗传学方法来阐明这些蛋白的功能和调控机制。Opa1通过与Mfn1合作参与线粒体融合的调控。此外，Opa1独立于线粒体融合调控凋亡的嵴重塑途径。由内膜菱形蛋白酶Parl产生的膜结合型和可溶性Opa1寡聚体在凋亡早期被破坏，导致线粒体嵴重塑和线粒体细胞色素c重新分布。Parl基因敲除小鼠的表型证实了该途径的重要性，该小鼠在多个组织中表现出过度凋亡。缺乏Parl的细胞对凋亡刺激更敏感，重新引入可溶性Opa1可挽救其表型。
