Selective linkage of mitochondrial enzymes to intracellular calcium stores differs between human-induced pluripotent stem cells, neural stem cells, and neurons
Selective linkage of mitochondrial enzymes to intracellular calcium stores differs between human-induced pluripotent stem cells, neural stem cells, and neurons
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DOI：
10.1111/jnc.15160
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发表时间：
2020-09-12
影响因子：
4.7
通讯作者：
Gibson, Gary E.
中科院分区：
文献类型：
--
作者：
Chen, Huanlian;Cross, Abigail C.;Gibson, Gary E.
线粒体和可释放的内质网（ER）钙调节神经元钙信号传导，且两者在阿尔茨海默病（AD）中均发生变化。阿尔茨海默病患者的成纤维细胞以及多种阿尔茨海默病模型中，内质网中可释放的钙库增加。α - 酮戊二酸脱氢酶复合物（KGDHC）是一种关键的线粒体酶复合物，其活性在阿尔茨海默病患者的大脑中降低，并且可能与斑块和缠结有关。我们之前在细胞系和小鼠神经元中的研究表明，KGDHC的减少会增加内质网可释放的钙库。这些研究的目的是测试这种关系在人诱导多能干细胞（iPSC）衍生的神经元中是否成立。抑制KGDHC 1小时或24小时分别使人类神经元内质网可释放的钙库增加69%和144%。这种作用是线粒体酶特异性的，因为抑制丙酮酸脱氢酶复合物（另一种关键的线粒体酶复合物）会减少内质网可释放的钙库。KGDHC与内质网可释放钙库的联系具有细胞类型特异性，因为这种相互作用在诱导多能干细胞或神经干细胞中不存在。因此，这些在人类神经元中的研究证实了KGDHC与内质网可释放钙库之间的联系，并支持使用人类神经元来研究阿尔茨海默病的机制和潜在治疗方法。
Mitochondria and releasable endoplasmic reticulum (ER) calcium modulate neuronal calcium signaling, and both change in Alzheimer's disease (AD). The releasable calcium stores in the ER are exaggerated in fibroblasts from AD patients and in multiple models of AD. The activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a key mitochondrial enzyme complex, is diminished in brains from AD patients, and can be plausibly linked to plaques and tangles. Our previous studies in cell lines and mouse neurons demonstrate that reductions in KGDHC increase the ER releasable calcium stores. The goal of these studies was to test whether the relationship was true in human iPSC-derived neurons. Inhibition of KGDHC for one or 24 hr increased the ER releasable calcium store in human neurons by 69% and 144%, respectively. The effect was mitochondrial enzyme specific because inhibiting the pyruvate dehydrogenase complex, another key mitochondrial enzyme complex, diminished the ER releasable calcium stores. The link of KGDHC to ER releasable calcium stores was cell type specific as the interaction was not present in iPSC or neural stem cells. Thus, these studies in human neurons verify a link between KGDHC and releasable ER calcium stores, and support the use of human neurons to examine mechanisms and potential therapies for AD.