Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase
Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase
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DOI：
10.1073/pnas.0808953105
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发表时间：
2008-12-30
影响因子：
11.1
通讯作者：
Hajnoczky, Gyorgy
中科院分区：
文献类型：
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作者：
Saotome, Masao;Safiulina, Dzhamilja;Hajnoczky, Gyorgy
钙振荡抑制线粒体沿微管的沿着运动，以支持线粒体的按需分布。为了激活这种机制，Ca 2+靶向一种尚未鉴定的细胞质因子，该因子似乎不是微管马达或激酶/磷酸酶。在这里，我们已经研究了依赖于线粒体动力学的米罗GTP酶，驻留在线粒体中，并包含两个EF-手Ca 2+结合域，在H9 c2细胞和原代神经元。在静息细胞质[Ca 2 +]（[Ca 2 +]（c）），线粒体的运动被Miro过表达增强，与EF-手的存在无关。Ca 2+诱导的线粒体运动的逮捕也促进米罗过度表达和抑制时，无论是米罗耗尽或他们的EF-手突变。Miro还增强了静息[Ca 2 +] c时线粒体的融合状态，但在高[Ca 2 +] c时促进线粒体碎片化。Miro对线粒体形态的这些影响似乎分别涉及Drp 1抑制和激活。在原代神经元中，Miro还引起树突状线粒体质量的增加和线粒体钙信号的增强。因此，Miro蛋白作为一个[Ca 2 +]（c）敏感的开关和双功能调节器的运动和融合裂变动力学的线粒体。
Calcium oscillations suppress mitochondrial movements along the microtubules to support on-demand distribution of mitochondria. To activate this mechanism, Ca2+ targets a yet unidentified cytoplasmic factor that does not seem to be a microtubular motor or a kinase/phosphatase. Here, we have studied the dependence of mitochondrial dynamics on the Miro GTPases that reside in the mitochondria and contain two EF-hand Ca2+-binding domains, in H9c2 cells and primary neurons. At resting cytoplasmic [Ca2+]([Ca2+](c)), movements of the mitochondria were enhanced by Miro overexpression irrespective of the presence of the EF-hands. The Ca2+-induced arrest of mitochondrial motility was also promoted by Miro overexpression and was suppressed when either the Miro were depleted or their EF-hand was mutated. Miro also enhanced the fusion state of the mitochondria at resting [Ca2+] c but promoted mitochondrial fragmentation at high [Ca2+] c. These effects of Miro on mitochondrial morphology seem to involve Drp1 suppression and activation, respectively. In primary neurons, Miro also caused an increase in dendritic mitochondrial mass and enhanced mitochondrial calcium signaling. Thus, Miro proteins serve as a [Ca2+](c)- sensitive switch and bifunctional regulator for both the motility and fusion-fission dynamics of the mitochondria.