Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
Cell Death Differ. 2013 Jan;20(1):139-53. doi: 10.1038/cdd.2012.106. Epub 2012 Sep 7.
Mitochondria are highly motile organelles that constantly undergo fission and fusion. Impairment of mitochondrial dynamics is associated with mitochondrial dysfunction and is frequently linked to the pathogenesis of neurodegenerative diseases and cancer. We have previously shown that biallelic inactivation of the suppressor of cytokine signaling 6 (SOCS6) gene is a frequent event in human gastric cancer. In this study, we recapitulated the event of SOCS6 loss using a Lentivirus-based knockdown approach, and demonstrated the linkage between SOCS6 depletion and the suppression of programmed cell death. SOCS6 promotes intrinsic apoptosis, with increased Bax conformational change, mitochondrial targeting, and oligomerization. Most importantly, SOCS6 is targeted to mitochondria and induces mitochondrial fragmentation mediated through an increase in DRP1 fission activity. Here, we show that SOCS6 forms complex with DRP1 and the mitochondrial phosphatase PGAM5, attenuates DRP1 phosphorylation, and promotes DRP1 mitochondrial translocation. Based on mutation analyses, SOCS6-mediated apoptosis is tightly coupled to its ability to induce mitochondrial fission. This study demonstrates an important role for SOCS6 in modulating mitochondrial dynamics and apoptosis.
线粒体是高度动态的细胞器，不断经历裂变和融合。线粒体动力学的损伤与线粒体功能障碍有关，并且经常与神经退行性疾病和癌症的发病机制有关。我们之前已经表明，细胞因子信号转导抑制因子 6（SOCS6）基因的双等位基因失活是人类胃癌中的常见事件。在这项研究中，我们使用基于慢病毒的敲低方法重现了 SOCS6 缺失的事件，并证明了 SOCS6 耗竭与程序性细胞死亡的抑制之间的联系。SOCS6 促进内在凋亡，Bax 构象变化、线粒体靶向和寡聚化增加。最重要的是，SOCS6 定位于线粒体，并通过增加 DRP1 分裂活性诱导线粒体碎片化。在这里，我们表明 SOCS6 与 DRP1 和线粒体磷酸酶 PGAM5 形成复合物，减弱 DRP1 的磷酸化，并促进 DRP1 线粒体易位。基于突变分析，SOCS6 介导的凋亡与其诱导线粒体分裂的能力紧密相关。这项研究表明 SOCS6 在调节线粒体动力学和凋亡方面起着重要作用。
