Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: The role of Ras
Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: The role of Ras
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DOI：
10.1016/j.mito.2009.02.005
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发表时间：
2009-06-01
期刊：
影响因子：
4.4
通讯作者：
Scorrano, Luca
中科院分区：
文献类型：
--
作者：
de Brito, Olga Martins;Scorrano, Luca
内质网（ER）和线粒体之间的通讯是至关重要的钙稳态，脂质的生物合成，并因此为线粒体代谢和细胞凋亡的调节。线粒体GTP酶mitofusin（MFN）2在线粒体相关膜（MAM）中富集，并且也定位于ER上，在ER上它与线粒体上的mitofusins相互作用以形成细胞器间桥。MFN 2还结合并抑制控制增殖、细胞周期和形态的原癌基因Ras。缺乏Ras结合域的MFN 2突变体无法束缚这两个细胞器，这就提出了Ras下游的信号级联是否会影响其将ER和线粒体并置的能力的问题。在这里，我们表明，细胞外调节激酶（ERK）1是过度激活的细胞缺乏MFN 2。然而，Ras-MAPK-ERK级联的遗传或药理学操作不影响ER和线粒体的形态或它们的束缚。因此，持续的Ras信号传导不是MFN 2损失影响细胞器形状和并置的机制，巩固了MFN 2在这些过程中的直接作用。(C)2009 Elsevier B. V.和线粒体研究学会。All rights reserved.
Communication between endoplasmic reticulum (ER) and mitochondria is crucial for Ca2+ homeostasis, lipid biosynthesis and therefore for the regulation of mitochondrial metabolism and apoptosis. The mitochondrial GTPase mitofusin (MFN) 2 is enriched in mitochondria associated membranes (MAM) and localizes also on the ER, where it interacts with mitofusins on mitochondria to form interorganellar bridges. MFN2 also binds and inhibits the proto-oncogene Ras that controls proliferation, cell cycle and morphology. Mutants of MFN2 lacking the Ras-binding domain fail to tether the two organelles, raising the question of whether signaling cascades downstream of Ras can influence its ability to juxtapose ER and mitochondria. Here we show that extracellular regulated kinase (ERK) 1 is hyperactivated in cells lacking MFN2. However, genetic or pharmacological manipulation of the Ras-MAPK-ERK cascade does not influence the morphology of ER and mitochondria or their tethering. Thus, sustained Ras signaling is not the mechanism through which loss of MFN2 affects organelle shape and juxtaposition, solidifying a direct role for MFN2 in these processes. (C) 2009 Elsevier B.V. and Mitochondria Research Society. All rights reserved.