Garofalo T, Giammarioli A M, Misasi R, Tinari A, Manganelli V, Gambardella L, Pavan A, Malorni W, Sorice M
Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Rome, Italy.
Cell Death Differ. 2005 Nov;12(11):1378-89. doi: 10.1038/sj.cdd.4401672.
Plasma membrane lipid microdomains have been considered as a sort of 'closed chamber', where several subcellular activities, including CD95/Fas-mediated proapoptotic signaling, take place. In this work we detected GD3 and GM3 gangliosides in isolated mitochondria from lymphoblastoid CEM cells. Moreover, we demonstrated the presence of microdomains in mitochondria by immunogold transmission electron microscopy. We also showed that GD3, the voltage-dependent anion channel-1 (VDAC-1) and the fission protein hFis1 are structural components of a multimolecular signaling complex, in which Bcl-2 family proteins (t-Bid and Bax) are recruited. The disruption of lipid microdomains in isolated mitochondria by methyl-beta-cyclodextrin prevented mitochondria depolarization induced by GD3 or t-Bid. Thus, mitochondrion appears as a subcompartmentalized organelle, in which microdomains may act as controllers of their apoptogenic programs, including fission-associated morphogenetic changes, megapore formation and function. These results disclose a new scenario in which mitochondria-associated lipid microdomains can act as regulators and catalysts of cell fate.
质膜脂质微区被认为是一种“封闭腔室”，包括CD95/Fas介导的促凋亡信号传导在内的多种亚细胞活动在此发生。在这项工作中，我们在淋巴母细胞样CEM细胞的分离线粒体中检测到了GD3和GM3神经节苷脂。此外，我们通过免疫金透射电子显微镜证明了线粒体中存在微区。我们还表明，GD3、电压依赖性阴离子通道1（VDAC-1）和裂变蛋白hFis1是多分子信号复合物的结构成分，其中招募了Bcl-2家族蛋白（t-Bid和Bax）。甲基-β-环糊精对分离线粒体中脂质微区的破坏阻止了由GD3或t-Bid诱导的线粒体去极化。因此，线粒体似乎是一个亚区室化的细胞器，其中微区可能作为其凋亡程序的控制器，包括与裂变相关的形态发生变化、大孔形成和功能。这些结果揭示了一种新的情况，即线粒体相关脂质微区可以作为细胞命运的调节因子和催化剂。
