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

A wide range of Ca -mediated functions are enabled by the dynamic properties of Ca , 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 R1 and downregulates its ligand binding, modulating ER-mitochondria Ca transfer through the MAM. The disrupted regulation of Ca transfer caused by DISC1 dysfunction leads to abnormal Ca accumulation in mitochondria following oxidative stress, which impairs mitochondrial functions. DISC1 dysfunction alters corticosterone-induced mitochondrial Ca accumulation in an oxidative stress-dependent manner. Together, these findings link stress-associated neural stimuli with intracellular ER-mitochondria Ca 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.