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Selective linkage of mitochondrial enzymes to intracellular calcium stores differs between human‐induced pluripotent stem cells, neural stem cells, and neurons
Author(s) -
Chen Huanlian,
Cross Abigail C.,
Thakkar Ankita,
Xu Hui,
Li Aiqun,
Paull Dan,
Noggle Scott A.,
Kruger Laken,
Denton Travis T.,
Gibson Gary E.
Publication year - 2021
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.15160
Subject(s) - mitochondrion , microbiology and biotechnology , calcium , biology , induced pluripotent stem cell , neural stem cell , calcium signaling , stem cell , endoplasmic reticulum , calcium in biology , cell type , calcium imaging , cell , neuroscience , intracellular , biochemistry , medicine , embryonic stem cell , gene
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.