Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape.
Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape.
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系统建模预测，线粒体接触位点调节突触后能量景观。
DOI：
10.1038/s41540-021-00185-7
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发表时间：
2021-06-02
影响因子：
4
通讯作者：
Rangamani P
中科院分区：
文献类型：
--
作者：
Leung A;Ohadi D;Pekkurnaz G;Rangamani P
钙动力学的时空区隔对神经元功能，特别是突触后棘的功能至关重要。这种精致水平的Ca2+区室化是通过Ca2+的储存和释放从各种胞内细胞器，特别是内质网（ER）和线粒体实现的。线粒体和内质网是控制神经元Ca2+动态的既定存储细胞器。线粒体也产生了突触后棘中使用的大部分能量，以支持与神经元刺激相关的下游事件。最近，高分辨率显微镜揭示了内质网和线粒体（MERCs）之间的直接接触位点，这些位点直接将Ca2+从内质网释放到线粒体膜中。在这项研究中，我们开发了一个计算三维反应-扩散模型来研究merc在调节Ca2+和ATP动力学中的作用。该时空模型解释了由谷氨酸刺激代谢和嗜离子性谷氨酸受体引发的Ca2+振荡，以及四个不同区室（细胞质、内质网、线粒体和MERC微域）中的Ca2+变化。我们的模拟预测这些细胞器的组织和细胞器间接触位点在调节Ca2+和ATP动力学中起关键作用。我们进一步表明，几何结构（线粒体和MERC）和代谢参数（胞质ATP水解，ATP生成）之间的串扰影响神经元的能量状态。我们的发现揭示了细胞器相互作用在预测突触信号中的Ca2+动力学中的重要性。总的来说，我们的模型预测，MERC连锁和线粒体大小的结合是胞质溶胶中最佳ATP生产所必需的。
Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in postsynaptic spines. This exquisite level of Ca2+ compartmentalization is achieved through the storage and release of Ca2+ from various intracellular organelles particularly the endoplasmic reticulum (ER) and the mitochondria. Mitochondria and ER are established storage organelles controlling Ca2+ dynamics in neurons. Mitochondria also generate a majority of energy used within postsynaptic spines to support the downstream events associated with neuronal stimulus. Recently, high resolution microscopy has unveiled direct contact sites between the ER and the mitochondria (MERCs), which directly channel Ca2+ release from the ER into the mitochondrial membrane. In this study, we develop a computational 3D reaction-diffusion model to investigate the role of MERCs in regulating Ca2+ and ATP dynamics. This spatiotemporal model accounts for Ca2+ oscillations initiated by glutamate stimulus of metabotropic and ionotropic glutamate receptors and Ca2+ changes in four different compartments: cytosol, ER, mitochondria, and the MERC microdomain. Our simulations predict that the organization of these organelles and inter-organellar contact sites play a key role in modulating Ca2+ and ATP dynamics. We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the neuronal energy state. Our findings shed light on the importance of organelle interactions in predicting Ca2+ dynamics in synaptic signaling. Overall, our model predicts that a combination of MERC linkage and mitochondria size is necessary for optimal ATP production in the cytosol.
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影响因子：
11.4
作者：
Area-Gomez, Estela;Castillo, Maria Del Carmen Lara;Tambini, Marc D.;Guardia-Laguarta, Cristina;de Groof, Ad J. C.;Madra, Moneek;Ikenouchi, Junichi;Umeda, Masato;Bird, Thomas D.;Sturley, Stephen L.;Schon, Eric A.
通讯作者：
Schon, Eric A.
影响因子：
19
作者：
Csordás G;Weaver D;Hajnóczky G
通讯作者：
Hajnóczky G
影响因子：
5.3
作者：
Cooney, JR;Hurlburt, JL;Fiala, JC
通讯作者：
Fiala, JC
影响因子：
3
作者：
Blackwell, Kim T.
通讯作者：
Blackwell, Kim T.
树突状棘的超微结构：突触和脊柱形态之间的相关性。
影响因子：
4.3
作者：
Arellano JI;Benavides-Piccione R;Defelipe J;Yuste R
通讯作者：
Yuste R