Activity-dependent subcellular compartmentalization of dendritic mitochondria structure in CA1 pyramidal neurons.
Activity-dependent subcellular compartmentalization of dendritic mitochondria structure in CA1 pyramidal neurons.
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CA1 锥体神经元树突状线粒体结构的活性依赖性亚细胞区室化。
DOI：
10.1101/2023.03.25.534233
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
LewisJr,TommyL
中科院分区：
文献类型：
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作者：
Virga,DanielM;Hamilton,Stevie;Osei,Bertha;Morgan,Abigail;Zamponi,Emiliano;Park,NatalieJ;Hewitt,VictoriaL;Zhang,David;Gonzalez,KevinC;Bloss,Erik;Polleux,Franck;LewisJr,TommyL
神经元线粒体在 ATP 生成之外发挥着重要作用，包括 Ca2+ 吸收，因此在突触功能和神经元反应特性中具有指导作用。给定神经元亚型的轴突和树突中的线粒体形态存在显着差异，但在海马 CA1 锥体神经元 (PN) 中，树突乔木内的线粒体也表现出显着程度的亚细胞、层特异性区室化。在这些神经元的树突中，线粒体形态范围从顶端簇中高度融合和拉长，到顶端斜向和基底树突区室中更加破碎，因此占据的树突体积比顶端簇中更小。然而，线粒体形态的这种惊人程度的亚细胞区室化背后的分子机制尚不清楚，因此无法评估其对神经元功能的影响。在这里，我们证明树突状线粒体的这种区室特异性形态需要 AMPK 的活性依赖性、Camkk2 依赖性激活及其磷酸化两个直接效应子的能力：促裂变 Drp1 受体 Mff 和最近鉴定的抗融合、Opa1 抑制蛋白 Mtfr1l。我们的研究揭示了一种新的活性依赖性分子机制，通过空间精确调节线粒体裂变/融合平衡，在体内神经元树突中线粒体形态的极端亚细胞区隔化。
Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly in the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a new activity-dependent molecular mechanism underlying the extreme subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise regulation of mitochondria fission/fusion balance.