State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73126, USA.
Cell Death Differ. 2020 Mar;27(3):1036-1051. doi: 10.1038/s41418-019-0396-4. Epub 2019 Jul 31.
Mitochondria are highly dynamic organelles and respond to stress by changing their fission-fusion cycle, undergoing mitophagy, or releasing apoptotic proteins to initiate cell death. The molecular mechanisms that sense different stresses and coordinate distinct effectors still await full characterization. Here, we show that PGAM5, which exists in an equilibrium between dimeric and multimeric states, dephosphorylates BCL-xL to inhibit apoptosis or FUNDC1 to activate mitofission and mitophagy in response to distinct stresses. In vinblastine-treated cells, PGAM5 dephosphorylates BCL-xL at Ser62 to restore BCL-xL sequestration of BAX and BAK and thereby resistance to apoptosis. Selenite-induced oxidative stress increases the multimerization of PGAM5, resulting in its dissociation from BCL-xL, which causes increased BCL-xL phosphorylation and apoptosis. Once freed, the more multimeric and active PGAM5 dephosphorylates FUNDC1 to initiate mitofission and mitophagy. The reciprocal interaction of PGAM5 with FUNDC1 and BCL-xL, controlled by PGAM5 multimerization, serves as a molecular switch between mitofission/mitophagy and apoptosis.
线粒体是高度动态的细胞器，通过改变其分裂-融合循环、进行线粒体自噬或释放凋亡蛋白来启动细胞死亡来应对应激。感知不同应激并协调不同效应器的分子机制仍有待充分表征。在这里，我们表明，PGAM5 存在于二聚体和多聚体状态之间的平衡中，它可以通过去磷酸化 BCL-xL 来抑制凋亡，或通过 FUNDC1 来激活线粒体裂变和线粒体自噬，以响应不同的应激。在长春新碱处理的细胞中，PGAM5 将 BCL-xL 上的丝氨酸 62 去磷酸化，以恢复 BCL-xL 对 BAX 和 BAK 的隔离，从而抵抗凋亡。亚硒酸盐诱导的氧化应激会增加 PGAM5 的多聚化，导致其与 BCL-xL 分离，从而导致 BCL-xL 磷酸化增加和凋亡。一旦被释放，更多的多聚化和活性 PGAM5 去磷酸化 FUNDC1 以启动线粒体裂变和线粒体自噬。PGAM5 与 FUNDC1 和 BCL-xL 的相互作用受 PGAM5 多聚化控制，是线粒体裂变/自噬和凋亡之间的分子开关。
