Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics
Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics
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DOI：
10.1073/pnas.1208141109
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发表时间：
2012-09-18
影响因子：
11.1
通讯作者：
Knoell, Bernd
中科院分区：
文献类型：
--
作者：
Beck, Henning;Flynn, Kevin;Knoell, Bernd
异常的线粒体功能、形态和转运是神经退行性疾病的主要特征。迄今为止，神经元内的线粒体运输被认为主要依赖于微管，而肌动蛋白可能介导短距离运动和线粒体锚定。在这里，我们分析了肌动蛋白对神经元线粒体大小和定位的影响。肌动蛋白增强神经突和生长锥的线粒体大小和数量。与此相反，提高G-肌动蛋白导致线粒体碎片和线粒体丰度下降。细胞F-肌动蛋白/G-肌动蛋白水平也调节血清反应因子（SRF）介导的基因调控，这表明SRF和线粒体动力学之间可能存在联系。事实上，SRF缺陷的神经元显示线粒体的神经退行性特征，包括破坏的形态、碎片化和受损的线粒体运动以及ATP能量代谢。相反，组成型活性SRF-VP 16诱导线粒体网络的形成和挽救亨廷顿蛋白（HTT）受损的线粒体动力学。最后，SRF和肌动蛋白动力学通过肌动蛋白切割蛋白cofilin及其弹弓磷酸酶连接以调节神经元线粒体动力学。总之，我们的数据表明，SRF-cofilin-actin信号轴调节神经元线粒体功能。
Aberrant mitochondrial function, morphology, and transport are main features of neurodegenerative diseases. To date, mitochondrial transport within neurons is thought to rely mainly on microtubules, whereas actin might mediate short-range movements and mitochondrial anchoring. Here, we analyzed the impact of actin on neuronal mitochondrial size and localization. F-actin enhanced mitochondrial size and mitochondrial number in neurites and growth cones. In contrast, raising G-actin resulted in mitochondrial fragmentation and decreased mitochondrial abundance. Cellular F-actin/G-actin levels also regulate serum response factor (SRF)mediated gene regulation, suggesting a possible link between SRF and mitochondrial dynamics. Indeed, SRF-deficient neurons display neurodegenerative hallmarks of mitochondria, including disrupted morphology, fragmentation, and impaired mitochondrial motility, as well as ATP energy metabolism. Conversely, constitutively active SRF-VP16 induced formation of mitochondrial networks and rescued huntingtin (HTT)-impaired mitochondrial dynamics. Finally, SRF and actin dynamics are connected via the actin severing protein cofilin and its slingshot phosphatase to modulate neuronal mitochondrial dynamics. In summary, our data suggest that the SRF-cofilin-actin signaling axis modulates neuronal mitochondrial function.