Department of Molecular, Cell and Cancer Biology
Cell Biology | Cellular and Molecular Physiology | Molecular and Cellular Neuroscience
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 IP3R1 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.
Ca(2+), DISC1, IP(3)R1, MAM, mitochondria, oxidative stress
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Copyright 2017 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
Cell Rep. 2017 Dec 5;21(10):2748-2759. doi: 10.1016/j.celrep.2017.11.043. Link to article on publisher's site
Park, Sung Jin; Lee, Su Been; Suh, Yeongjun; Kim, Su-Jeong; Lee, Namgyu; Hong, Ji-Ho; Park, Cana; Woo, Youngsik; Ishizuka, Koko; Kim, Joung-Hun; Berggren, Per-Olof; Sawa, Akira; and Park, Sang Ki, "DISC1 Modulates Neuronal Stress Responses by Gate-Keeping ER-Mitochondria Ca(2+) Transfer through the MAM" (2017). Open Access Articles. 3329.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.