DISC1 Modulates Neuronal Stress Responses by Gate-Keeping ER-Mitochondria Ca 2+ Transfer through the MAM.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Cambridge, MA] : Cell Press, c 2012-
    • Subject Terms:
      Calcium/*metabolism ; Endoplasmic Reticulum/*metabolism ; Intracellular Membranes/*metabolism ; Nerve Tissue Proteins/*metabolism ; Neurons/*metabolism; Animals ; Cell Line ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Nerve Tissue Proteins/genetics ; Oxidative Stress/physiology
    • Abstract:
      A wide range of Ca 2+ -mediated functions are enabled by the dynamic properties of Ca 2+ , all of which are dependent on the endoplasmic reticulum (ER) and mitochondria. Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that is involved in the function of intracellular organelles and is linked to cognitive and emotional deficits. Here, we demonstrate that DISC1 localizes to the mitochondria-associated ER membrane (MAM). At the MAM, DISC1 interacts with IP 3 R1 and downregulates its ligand binding, modulating ER-mitochondria Ca 2+ transfer through the MAM. The disrupted regulation of Ca 2+ transfer caused by DISC1 dysfunction leads to abnormal Ca 2+ accumulation in mitochondria following oxidative stress, which impairs mitochondrial functions. DISC1 dysfunction alters corticosterone-induced mitochondrial Ca 2+ accumulation in an oxidative stress-dependent manner. Together, these findings link stress-associated neural stimuli with intracellular ER-mitochondria Ca 2+ crosstalk via DISC1, providing mechanistic insight into how environmental risk factors can be interpreted by intracellular pathways under the control of genetic components in neurons.
      (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Ca(2+); DISC1; IP(3)R1; MAM; mitochondria; oxidative stress
    • Accession Number:
      0 (DISC1 protein, human)
      0 (Disc1 protein, mouse)
      0 (Nerve Tissue Proteins)
      SY7Q814VUP (Calcium)
    • Publication Date:
      Date Created: 20171207 Date Completed: 20180717 Latest Revision: 20180717
    • Publication Date:
      20221213
    • Accession Number:
      10.1016/j.celrep.2017.11.043
    • Accession Number:
      29212023