Cecchi Cristina, Baglioni Serena, Fiorillo Claudia, Pensalfini Anna, Liguri Gianfranco, Nosi Daniele, Rigacci Stefania, Bucciantini Monica, Stefani Massimo
Department of Biochemical Sciences.
J Cell Sci. 2005 Aug 1;118(Pt 15):3459-70. doi: 10.1242/jcs.02473.
It has been reported that different tissue or cultured cell types are variously affected by the exposure to toxic protein aggregates, however a substantial lack of information exists about the biochemical basis of cell resistance or susceptibility to the aggregates. We investigated the extent of the cytotoxic effects elicited by supplementing the media of a panel of cultured cell lines with aggregates of HypF-N, a prokaryotic domain not associated with any amyloid disease. The cell types exposed to early, pre-fibrillar aggregates (not mature fibrils) displayed variable susceptibility to damage and to apoptotic death with a significant inverse relation to membrane content in cholesterol. Susceptibility to damage by the aggregates was also found to be significantly related to the ability of cells to counteract early modifications of the intracellular free Ca2+ and redox status. Accordingly, cell resistance appeared related to the efficiency of the biochemical equipment leading any cell line to sustain the activity of Ca2+ pumps while maintaining under control the oxidative stress associated with the increased metabolic rate. Our data depict membrane destabilization and the subsequent early derangement of ion balance and intracellular redox status as key events in targeting exposed cells to apoptotic death.
据报道，不同的组织或培养的细胞类型受有毒蛋白质聚集体暴露的影响各不相同，然而，关于细胞对聚集体抗性或敏感性的生化基础，存在大量信息缺失。我们研究了用原核结构域HypF-N的聚集体补充一组培养细胞系培养基所引发的细胞毒性作用程度，HypF-N与任何淀粉样疾病均无关联。暴露于早期、预纤维化聚集体（而非成熟纤维）的细胞类型对损伤和凋亡死亡表现出不同的敏感性，且与胆固醇膜含量呈显著负相关。还发现细胞对聚集体损伤的敏感性与细胞抵消细胞内游离Ca2+和氧化还原状态早期变化的能力显著相关。因此，细胞抗性似乎与生化机制的效率有关，该机制使任何细胞系在维持Ca2+泵活性的同时，控制与代谢率增加相关的氧化应激。我们的数据表明，膜不稳定以及随后离子平衡和细胞内氧化还原状态的早期紊乱是导致暴露细胞凋亡死亡的关键事件。
