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.

中文翻译：

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线粒体酶与细胞内钙存储的选择性连接在人诱导的多能干细胞，神经干细胞和神经元之间有所不同

线粒体和可释放的内质网（ER）钙调节神经元钙信号传导，并且两者都在阿尔茨海默氏病（AD）中发生变化。内质网中可释放的钙储存在来自AD患者的成纤维细胞中和在多种AD模型中被夸大。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AD患者的大脑中已减弱，并且可能与斑块和缠结有关。我们先前在细胞系和小鼠神经元中的研究表明，降低KGDHC可以增加ER释放的钙存储。这些研究的目的是检验在人iPSC衍生的神经元中这种关系是否正确。抑制KGDHC 1或24小时后，人神经元中ER可释放的钙存储量分别增加了69％和144％。该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）可减少ER释放的钙存储。由于iPSC或神经干细胞中不存在相互作用，因此KGDHC与ER可释放钙存储之间的联系是特定于细胞类型的。因此，这些在人类神经元中的研究证实了KGDHC与可释放的ER钙存储之间的联系，并支持使用人类神经元来检查AD的机制和潜在疗法。