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

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.