The abundance of the ARL2 GTPase and its GAP, ELMOD2, at mitochondria are modulated by the fusogenic activity of mitofusins and stressors.
The abundance of the ARL2 GTPase and its GAP, ELMOD2, at mitochondria are modulated by the fusogenic activity of mitofusins and stressors.
复制标题
线粒体中 ARL2 GTP 酶及其 GAP、ELMOD2 的丰度受线粒体融合素和应激源的融合活性调节。
DOI：
10.1371/journal.pone.0175164
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Kahn RA
中科院分区：
文献类型：
--
作者：
Newman LE;Schiavon CR;Zhou C;Kahn RA
线粒体是必要的、动态的细胞器，它对许多应激源作出反应，其形态变化与几种线粒体功能有关，尽管所涉及的机制尚不清楚。我们发现，在因丝裂酶2 （MFN2）而缺失的永活小鼠胚胎成纤维细胞中，调节GTPase ARL2及其GAP ELMOD2的水平在线粒体中特异性升高，而非MFN1。在因MFN2而缺失的mef中，升高的ARL2和ELMOD2可以通过重新引入MFN2来逆转，但前提是这些mef中的线粒体断裂也被逆转，这表明ARL2和ELMOD2升高的逆转需要MFN2的促聚变活性。研究人员还研究了与线粒体形态相关的其他应激源，其中包括葡萄糖或血清剥夺，也会导致ARL2和ELMOD2升高。相反，一些能量代谢的药理学抑制剂引起ARL2升高，但不影响ELMOD2水平。总之，我们将这些数据解释为线粒体中存在两种arl2敏感通路的证据，一种影响ATP水平，不依赖于ELMOD2，另一种导致涉及ELMOD2的MFN2的线粒体融合。
Mitochondria are essential, dynamic organelles that respond to a number of stressors with changes in morphology that are linked to several mitochondrial functions, though the mechanisms involved are poorly understood. We show that the levels of the regulatory GTPase ARL2 and its GAP, ELMOD2, are specifically increased at mitochondria in immortalized mouse embryo fibroblasts deleted for Mitofusin 2 (MFN2), but not MFN1. Elevated ARL2 and ELMOD2 in MEFs deleted for MFN2 could be reversed by re-introduction of MFN2, but only when the mitochondrial fragmentation in these MEFs was also reversed, demonstrating that reversal of elevated ARL2 and ELMOD2 requires the fusogenic activity of MFN2. Other stressors with links to mitochondrial morphology were investigated and several, including glucose or serum deprivation, also caused increases in ARL2 and ELMOD2. In contrast, a number of pharmacological inhibitors of energy metabolism caused increases in ARL2 without affecting ELMOD2 levels. Together we interpret these data as evidence of two ARL2-sensitive pathways in mitochondria, one affecting ATP levels that is independent of ELMOD2 and the other leading to mitochondrial fusion involving MFN2 that does involve ELMOD2.