Impaired mitochondrial respiration promotes dendritic branching via the AMPK signaling pathway.
Impaired mitochondrial respiration promotes dendritic branching via the AMPK signaling pathway.
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DOI：
10.1038/cddis.2014.144
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发表时间：
2014-04-10
影响因子：
9
通讯作者：
Bano D
中科院分区：
文献类型：
--
作者：
Gioran A;Nicotera P;Bano D
功能性神经元回路需要不断重塑由高度互连的神经元组成的网络。突触的可塑性和精心制作的树突状分支的成形需要能量，因此依赖于有效的线粒体氧化磷酸化（OXPHOS）。树突状图案化的空间和功能调节也发生在细胞命运特化之后;然而，这一复杂过程背后的分子机制仍然难以捉摸。在这里，我们利用树突状结构的变化，在高度分支的神经元异常线粒体活动的结果。在秀丽隐杆线虫的感觉神经元中，线粒体复合物I亚基的遗传操作导致了树突状乔木和异位结构的意外生长。树突状分支的数量增加是通过特定的信号级联而不是作为氧化应激的简单结果来协调的。遗传和药理学证据的基础上，我们表明，OXPHOS缺陷促进通过激活AMP-活化蛋白激酶AMPK和下游靶磷酸肌醇3-激酶PI 3 K的分支。总之，我们的研究结果描述了一个明确的信号通路，调节树突状细胞的生长条件下受损的OXPHOS和所产生的AMPK激活。
Functional neuronal circuits require a constant remodeling of their network composed of highly interconnected neurons. The plasticity of synapses and the shaping of elaborated dendritic branches are energy demanding and therefore depend on an efficient mitochondrial oxidative phosphorylation (OXPHOS). The spatial and functional regulations of dendritic patterning occur also after cell fate specification; however, the molecular mechanisms underlying this complex process remain elusive. Here, we exploit the changes in dendritic architecture in highly branched neurons as a result of aberrant mitochondrial activity. In sensory neurons of Caenorhabditis elegans, genetic manipulations of mitochondrial complex I subunits cause an unexpected outgrowth of dendritic arbors and ectopic structures. The increased number of dendritic branches is coordinated through a specific signaling cascade rather than as a simple consequence of oxidative stress. On the basis of genetic and pharmacological evidence, we show that OXPHOS deficiency promotes branching through the activation of the AMP-activated protein kinase AMPK and the downstream target phosphoinositide 3-kinase PI3K. Taken together, our findings describe a well-defined signaling pathway that regulates dendritic outgrowth in conditions of compromised OXPHOS and the resulting AMPK activation.