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

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

Research output: Contribution to journalArticlepeer-review

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. 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.

Original languageEnglish (US)
Pages (from-to)2748-2759
Number of pages12
JournalCell Reports
Volume21
Issue number10
DOIs
StatePublished - Dec 5 2017

Keywords

  • Ca
  • DISC1
  • IPR1
  • MAM
  • mitochondria
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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