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Cell Rep. 2017 Dec 5;21(10):2748-2759. doi: 10.1016/j.celrep.2017.11.043.

DISC1 Modulates Neuronal Stress Responses by Gate-Keeping ER-Mitochondria Ca2+ Transfer through the MAM.

Author information

1
Department of Life Sciences, Pohang University of Science and Technology, 790-784 Pohang, Republic of Korea.
2
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
3
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, 790-784 Pohang, Republic of Korea; The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 171 76 Stockholm, Sweden.
5
Department of Life Sciences, Pohang University of Science and Technology, 790-784 Pohang, Republic of Korea. Electronic address: skpark@postech.ac.kr.

Abstract

A wide range of Ca2+-mediated functions are enabled by the dynamic properties of Ca2+, 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 Ca2+ transfer through the MAM. The disrupted regulation of Ca2+ transfer caused by DISC1 dysfunction leads to abnormal Ca2+ accumulation in mitochondria following oxidative stress, which impairs mitochondrial functions. DISC1 dysfunction alters corticosterone-induced mitochondrial Ca2+ accumulation in an oxidative stress-dependent manner. Together, these findings link stress-associated neural stimuli with intracellular ER-mitochondria Ca2+ 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.

KEYWORDS:

Ca(2+); DISC1; IP(3)R1; MAM; mitochondria; oxidative stress

PMID:
29212023
DOI:
10.1016/j.celrep.2017.11.043
[Indexed for MEDLINE]
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