Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis.
Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis.
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DOI：
10.1016/j.molcel.2015.02.021
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发表时间：
2015-04-16
期刊：
影响因子：
16
通讯作者：
Scorrano, Luca
中科院分区：
文献类型：
--
作者：
Pyakurel, Aswin;Savoia, Claudia;Hess, Daniel;Scorrano, Luca
线粒体形态的受控变化参与细胞信号级联。然而，改变线粒体形状的分子机制在很大程度上是未知的。在这里，我们表明，有丝分裂原活化蛋白（MAP）激酶级联成员细胞外信号调节激酶（ERK）磷酸化促融合蛋白mitofusin（MFN）1，调节其参与细胞凋亡和线粒体融合。磷酸化蛋白质组学和生物化学分析显示，MFN 1在其七肽重复序列（HR）1结构域的非典型ERK位点磷酸化。该位点被证明是通过MEK/ERK级联介导MFN 1依赖的线粒体延长和凋亡调节所必需的。一个突变体模仿组成型MFN 1磷酸化是低效率的寡聚化和线粒体拴系，但结合更积极的促凋亡BCL-2家族成员巴克，促进其激活和细胞死亡。此外，神经元凋亡后氧葡萄糖剥夺和MEK/ERK激活需要一个完整的MFN 1 T562。我们的数据确定MFN 1作为ERK靶点调节线粒体形状和凋亡。Mfn 1被ERK磷酸化以抑制线粒体融合Mfn 1磷酸化刺激线粒体透化和凋亡MAPK级联通过Mfn 1调节线粒体形状和凋亡Pyakurel et al.显示多效ERK激酶磷酸化线粒体融合蛋白Mitofusin 1。ERK的磷酸化抑制线粒体融合并刺激细胞凋亡线粒体透化，确定线粒体形状和细胞凋亡的方式
Controlled changes in mitochondrial morphology participate in cellular signaling cascades. However, the molecular mechanisms modifying mitochondrial shape are largely unknown. Here we show that the mitogen-activated protein (MAP) kinase cascade member extracellular-signal-regulated kinase (ERK) phosphorylates the pro-fusion protein mitofusin (MFN) 1, modulating its participation in apoptosis and mitochondrial fusion. Phosphoproteomic and biochemical analyses revealed that MFN1 is phosphorylated at an atypical ERK site in its heptad repeat (HR) 1 domain. This site proved essential to mediate MFN1-dependent mitochondrial elongation and apoptosis regulation by the MEK/ERK cascade. A mutant mimicking constitutive MFN1 phosphorylation was less efficient in oligomerizing and mitochondria tethering but bound more avidly to the proapoptotic BCL-2 family member BAK, facilitating its activation and cell death. Moreover, neuronal apoptosis following oxygen glucose deprivation and MEK/ERK activation required an intact MFN1T562. Our data identify MFN1 as an ERK target to modulate mitochondrial shape and apoptosis. Mfn1 is phosphorylated by ERK to inhibit mitochondrial fusion Mfn1 phosphorylation stimulates mitochondrial permeabilization and apoptosis The MAPK cascade regulates mitochondrial shape and apoptosis via Mfn1 Pyakurel et al. show that the pleiotropic ERK kinase phosphorylates the mitochondrial fusion protein Mitofusin 1. Phosphorylation by ERK inhibits mitochondrial fusion and stimulates apoptotic mitochondrial permeabilization, identifying how mitochondrial shape and apoptosis
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影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1073/pnas.0703976104
发表时间：
2007-07-10
影响因子：
11.1
作者：
Brooks, Craig;Wei, Qingqing;Dong, Zheng
通讯作者：
Dong, Zheng
DOI：
10.1073/pnas.0708959104
发表时间：
2007-11-13
影响因子：
11.1
作者：
Abramov, Andrey Y.;Fraley, Cresson;Pavlov, Evgeny
通讯作者：
Pavlov, Evgeny
影响因子：
11.4
作者：
Germain, M;Mathai, JP;Shore, GC
通讯作者：
Shore, GC
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca