Antimitotic drugs are extensively used in the clinics to treat different types of cancer. They can retain cells in a prolonged mitotic arrest imposing two major fates, mitotic slippage, or mitotic cell death. While the former is molecularly well characterized, the mechanisms that control mitotic cell death remain poorly understood. Here, we performed quantitative proteomics of HeLa cells under mitotic arrest induced with paclitaxel, a microtubule-stabilizer drug, to identify regulators of such cell fate decision. We identified alterations in several apoptosis-related proteins, among which the mitochondrial fission protein Drp1 presented increased levels. We found that Drp1 depletion during prolonged mitotic arrest led to strong mitochondrial depolarization and faster mitotic cell death as well as enhanced mitophagy, a mechanism to remove damaged mitochondria. Our findings support a new role of Drp1 in orchestrating the cellular stress responses during mitosis, where mitochondrial function and distribution into the daughter cells need to be coordinated with cell fate. This novel function of Drp1 in the cell cycle becomes best visible under conditions of prolonged mitotic arrest.

临床上广泛使用抗有丝分裂药物来治疗不同类型的癌症。它们可以在长时间的有丝分裂停滞中保留细胞，从而导致两种主要命运，有丝分裂滑脱或有丝分裂细胞死亡。虽然前者在分子上有很好的特征，但控制有丝分裂细胞死亡的机制仍然知之甚少。在这里，我们对紫杉醇（一种微管稳定剂药物）诱导的有丝分裂阻滞下的 HeLa 细胞进行了定量蛋白质组学，以确定这种细胞命运决定的调节因子。我们发现了几种细胞凋亡相关蛋白的改变，其中线粒体裂变蛋白 Drp1 的水平升高。我们发现在长时间的有丝分裂停滞期间 Drp1 的消耗导致强烈的线粒体去极化和更快的有丝分裂细胞死亡以及增强的线粒体自噬，一种去除受损线粒体的机制。我们的研究结果支持 Drp1 在有丝分裂期间协调细胞应激反应中的新作用，其中线粒体功能和分布到子细胞中需要与细胞命运相协调。Drp1 在细胞周期中的这种新功能在延长有丝分裂停滞的条件下变得最明显。