Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes.
Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes.
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DOI：
10.1016/j.neuron.2016.12.034
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发表时间：
2017-02-08
期刊：
影响因子：
16.2
通讯作者：
Bergles DE
中科院分区：
文献类型：
--
作者：
Agarwal A;Wu PH;Hughes EG;Fukaya M;Tischfield MA;Langseth AJ;Wirtz D;Bergles DE
星形胶质细胞扩展高度分支的过程，形成功能隔离的微域，通过重新分配、去除神经递质和释放影响血流和神经元活动的因子来促进局部稳态。微结构域表现出钙（Ca2+）的自发增加，但这种局部信号传导的机制和功能意义尚不清楚。通过培养条件，膜锚定的GCaMP3小鼠，我们发现，在内质网ip3依赖性释放缺失的情况下，微结构域的活性是通过线粒体通透性过渡孔短暂开放期间线粒体的Ca2+外溢产生的。氧化磷酸化过程中活性氧的产生促进了这些微结构域Ca2+瞬变，并通过超氧化物歧化酶1 （SOD1 G93A）突变形式的表达增强，这种突变形式导致肌萎缩性侧索硬化症（ALS）的星形细胞功能障碍和神经退行性变。通过将线粒体定位到微结构域，星形胶质细胞确保了对能量需求过程的局部代谢支持，并使代谢需求和Ca2+信号事件之间的耦合成为可能。
Astrocytes extend highly branched processes that form functionally isolated microdomains, facilitating local homeostasis by redistributing ions, removing neurotransmitters and releasing factors to influence blood flow and neuronal activity. Microdomains exhibit spontaneous increases in calcium (Ca2+), but the mechanisms and functional significance of this localized signaling are unknown. By developing conditional, membrane anchored GCaMP3 mice, we found that microdomain activity that occurs in the absence of IP3-dependent release from endoplasmic reticulum arises through Ca2+ efflux from mitochondria during brief openings of the mitochondrial permeability transition pore. These microdomain Ca2+ transients were facilitated by the production of reactive oxygen species during oxidative phosphorylation and enhanced by expression of a mutant form of superoxide dismutase 1 (SOD1 G93A) that causes astrocyte dysfunction and neurodegeneration in amyotrophic lateral sclerosis (ALS). By localizing mitochondria to microdomains, astrocytes ensure local metabolic support for energetically demanding processes and enable coupling between metabolic demand and Ca2+ signaling events.