We previously showed that fluorizoline, a fluorinated thiazoline compound, binds to both subunits of the mitochondrial prohibitin (PHB) complex, PHB1 and PHB2, being the expression of these proteins required for fluorizoline-induced apoptosis in mouse embryonic fibroblasts. To investigate the conservation of this apoptotic mechanism, we studied the effect of PHB downregulation on fluorizoline activity on two human cell lines, HEK293T and U2OS. Then, we asked whether PHBs mediate the effect of fluorizoline in a multicellular organism. Interestingly, reduced levels of PHBs in the human cells impaired the induction of apoptosis by fluorizoline. We observed that fluorizoline has a detrimental dose-dependent effect on the development and survival of the nematode model Caenorhabditis elegans. Besides, such effects of fluorizoline treatment in living nematodes were absent in PHB mutants. Finally, we further explored the apoptotic pathway triggered by fluorizoline in human cell lines. We found that the BH3-only proteins NOXA, BIM and PUMA participate in fluorizoline-induced apoptosis and that the induction of NOXA and PUMA is dependent on PHB expression.

我们之前发现氟唑啉是一种氟化噻唑啉化合物，它与线粒体抑制素 (PHB) 复合物的两个亚基 PHB1 和 PHB2 结合，这是氟唑啉诱导的小鼠胚胎成纤维细胞凋亡所需的这些蛋白质的表达。为了研究这种凋亡机制的保守性，我们研究了 PHB 下调对两种人类细胞系 HEK293T 和 U2OS 氟唑啉活性的影响。然后，我们询问 PHBs 是否介导氟唑啉在多细胞生物中的作用。有趣的是，人类细胞中 PHBs 水平的降低会损害氟唑啉对细胞凋亡的诱导。我们观察到氟唑啉对线虫模型秀丽隐杆线虫的发育和存活具有有害的剂量依赖性影响. 此外，在 PHB 突变体中不存在氟唑啉处理对活线虫的这种影响。最后，我们进一步探索了氟唑啉在人细胞系中触发的凋亡途径。我们发现仅 BH3 蛋白 NOXA、BIM 和 PUMA 参与氟唑啉诱导的细胞凋亡，并且 NOXA 和 PUMA 的诱导依赖于 PHB 表达。