School of Biochemistry, Centre for Synaptic Plasticity, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, BS8 1TD, UK.
Sci Rep. 2017 Mar 6;7:43811. doi: 10.1038/srep43811.
The GTPase dynamin-related protein 1 (Drp1) is essential for physiological and pathophysiological mitochondrial fission. DeSUMOylation of Drp1 by the enzyme SENP3 promotes cell death during reperfusion after ischaemia by enhancing Drp1 partitioning to the mitochondrial outer membrane (MOM), which causes cytochrome c release and apoptosis. However, how deSUMOylation recruits Drp1 to the MOM is unknown. Here we show that deSUMOylation selectively promotes Drp1 binding to the MOM resident adaptor protein mitochondrial fission factor (Mff). Consistent with this, preventing Drp1 SUMOylation by mutating the SUMO acceptor sites enhances binding to Mff. Conversely, increasing Drp1 SUMOylation by knocking down SENP3 reduces both Drp1 binding to Mff and stress-induced cytochrome c release. Directly tethering Drp1 to the MOM bypasses the need for Mff to evoke cytochrome c release, and occludes the effect of SENP3 overexpression. Thus, Drp1 deSUMOylation promotes cell death by enhancing Mff-mediated mitochondrial recruitment. These data provide a mechanistic explanation for how the SUMOylation status of Drp1 acts as a key switch in cell death/survival decisions following extreme cell stress.
GTPase 动力相关蛋白 1（Drp1）对于生理和病理生理线粒体裂变是必不可少的。酶 SENP3 对 Drp1 的去 SUMO 化作用通过增强 Drp1 向线粒体外膜（MOM）的分配，从而导致细胞色素 c 释放和细胞凋亡，促进缺血后再灌注期间的细胞死亡。然而，去 SUMO 化如何招募 Drp1 到 MOM 尚不清楚。在这里，我们表明去 SUMO 化选择性地促进 Drp1 与驻留在 MOM 上的衔接蛋白线粒体裂变因子（Mff）结合。与此一致，通过突变 SUMO 受体位点来阻止 Drp1 的 SUMO 化增强了与 Mff 的结合。相反，通过敲低 SENP3 增加 Drp1 的 SUMO 化，会降低 Drp1 与 Mff 的结合以及应激诱导的细胞色素 c 释放。直接将 Drp1 固定在 MOM 上绕过了 Mff 引发细胞色素 c 释放的需要，并阻断了 SENP3 过表达的作用。因此，Drp1 的去 SUMO 化通过增强 Mff 介导的线粒体募集来促进细胞死亡。这些数据为 Drp1 的 SUMO 化状态如何作为极端细胞应激后细胞死亡/存活决策的关键开关提供了机制解释。
