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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

Huanlian Chen, Ankita Thakkar, Abigail C. Cross, Hui Xu, Aiqun Li, Dan Pauli, Scott A. Noggle, Laken Kruger, Travis T. Denton, Gary E. Gibson
doi: https://doi.org/10.1101/2020.06.20.162040
Huanlian Chen
1Burke Neurological Institute, Brain and Mind Research Institute, Weill Cornell Medicine, White Plains, NY
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Ankita Thakkar
1Burke Neurological Institute, Brain and Mind Research Institute, Weill Cornell Medicine, White Plains, NY
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Abigail C. Cross
1Burke Neurological Institute, Brain and Mind Research Institute, Weill Cornell Medicine, White Plains, NY
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Hui Xu
1Burke Neurological Institute, Brain and Mind Research Institute, Weill Cornell Medicine, White Plains, NY
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Aiqun Li
2The New York Stem Cell Foundation Research Institute, New York, NY
4Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY
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Dan Pauli
2The New York Stem Cell Foundation Research Institute, New York, NY
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Scott A. Noggle
2The New York Stem Cell Foundation Research Institute, New York, NY
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Laken Kruger
3Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy and Pharmaceutical Sciences, Spokane, WA
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Travis T. Denton
3Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy and Pharmaceutical Sciences, Spokane, WA
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Gary E. Gibson
1Burke Neurological Institute, Brain and Mind Research Institute, Weill Cornell Medicine, White Plains, NY
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  • For correspondence: ggibson@med.cornell.edu
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Abstract

The coupling of the endoplasmic reticulum (ER) with mitochondria modulates neuronal calcium signaling. Whether this link changes with neuronal development is unknown. The current study first determined whether ER calcium stores are similar during development of human neurons, and then tested if the ER/mitochondrial coupling varied with development. The release of ER calcium to the cytosol by the IP3 agonist bradykinin was determined in human induced-pluripotent stem cells (iPSC), neural stem cells (NSC) and neurons. The concentration dependence for the release of ER calcium was similar at different stages of development. Metabolism changes dramatically with development. Glycolysis is the main energy source in iPSC and NSC whereas mitochondrial metabolism is more prominent in neurons. To test whether the coupling of mitochondria and ER changed with development, bombesin or bradykinin releasable calcium stores (BRCS) were monitored after inhibiting either of two key mitochondrial enzyme complexes: the alpha-ketoglutarate dehydrogenase complex (KGDHC) or the pyruvate dehydrogenase complex (PDHC). Inhibition of KGDHC did not alter BRCS in either iPSC or NSC. Inhibition of PDHC in neurons diminished BRCS whereas decreased KGDHC activity exaggerated BRCS. The latter finding may help understand the pathology of Alzheimer’s disease (AD). BRCS is exaggerated in cells from AD patients and KGDHC is reduced in brains of patients with AD. In summary, a prominent ER/mitochondrial link in neurons is associated with selective mitochondrial enzymes. The ER/mitochondrial link changes with human neuronal development and plausibly links ER calcium changes to AD.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations used

    AP
    alkaline-phosphatase
    APOE4
    epsilon 4 allele of Apolipoprotein E gene
    AD
    Alzheimer’s disease
    t-BIIP
    tert-butyl-hydroperoxide
    BRCS
    bombesin or bradykinin releasable calcium stores
    BSS
    balanced salt solution
    CESP
    carboxyethyl succinyl phosphonate
    DMAP
    dimethyl acetyl phosphonate
    ER
    endoplasmic reticulum
    HBSS
    Hank’s Balanced Salt Solution
    IP3
    inositol 1,4,5-trisphosphate
    IP3R
    inositol 1,4,5-trisphosphate receptors
    iPSC
    induced pluripotent stem cells
    KGDHC
    alpha-ketoglutarate dehydrogenase complex
    NEM
    neural expansion media
    NIM
    neural induction media
    NSC
    neural stem cells
    PDHC
    pyruvate dehydrogenase complex
    PS-1
    presenilin-1
    PTP
    permeability transition pore
    RRID
    research resource identifier (see scicrunch.org)
    RyR
    ryanodine receptors
    SNAP
    S-nitroso-N-acetylpenicillamine
    SP
    trisodium succinyl phosphonate
    STIM
    stromal interaction molecule
    TCA
    tricarboxylic acid cycle
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted June 20, 2020.
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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
    Huanlian Chen, Ankita Thakkar, Abigail C. Cross, Hui Xu, Aiqun Li, Dan Pauli, Scott A. Noggle, Laken Kruger, Travis T. Denton, Gary E. Gibson
    bioRxiv 2020.06.20.162040; doi: https://doi.org/10.1101/2020.06.20.162040
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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
    Huanlian Chen, Ankita Thakkar, Abigail C. Cross, Hui Xu, Aiqun Li, Dan Pauli, Scott A. Noggle, Laken Kruger, Travis T. Denton, Gary E. Gibson
    bioRxiv 2020.06.20.162040; doi: https://doi.org/10.1101/2020.06.20.162040

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