Fig. 2

Oxidative damage and mitochondria-associated membranes. (1) Under normal conditions, ER stress activates the UPR which acts to restore homeostasis. Oxidative and hormonal stress stimulate ER-to-Mitochondria Ca²⁺ transfer (via inositol triphosphate receptors (IP3Rs)). MAM proteins (SIGMAR-1 and DISC1) act to stabilize IP3Rs and limit overall mitochondrial calcium accumulation. Independently, DISC1 acts to counteract corticosterone-induced stress (HPA-axis overactivity) and SIGMAR-1 acts to inhibit pro-inflammatory gene expression (NF-kB) and assist in the formation of mature BDNF. (2) Mitochondrial dysfunction in BD leads to increased oxidative damage, overwhelming the UPR. SIGMAR-1/DISC dysfunction can lead to decreased BDNF expression, loss of feedback on hormonal/oxidative stress signals, and increased IP3R ligand binding (subsequently increasing calcium influx into mitochondria). Risk SNPs associated with the CACNA1C locus can lead to even greater Ca²⁺ activity, further overwhelming anti-apoptotic signals (bcl-2). (3) Taken together, this dysfunction leads to increased pro-inflammatory signaling, NLRP3 inflammasome assembly at the ER-mitochondrial border, and eventually apoptosis, pyropoptosis, or autophagy. Subsequent release of cellular contents can cause amplification of extracellular inflammatory signaling and neurotoxicity (detailed in Figs. 3 and 4)