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

Publication date: 5 December 2017
Source:Cell Reports, Volume 21, Issue 10
Author(s): Sung Jin Park, Su Been Lee, Yeongjun Suh, Su-Jeong Kim, Namgyu Lee, Ji-Ho Hong, Cana Park, Youngsik Woo, Koko Ishizuka, Joung-Hun Kim, Per-Olof Berggren, Akira Sawa, Sang Ki Park
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.

Graphical abstract

Teaser

Park et al. show that DISC1 regulates ER-mitochondria Ca²⁺ transfer through mitochondria-associated ER membrane (MAM). DISC1 dysfunction at MAM increases ER-mitochondria Ca²⁺ transfer during oxidative stress and excessive amounts of corticosterone, which impairs mitochondrial function.


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