Abstract
Compromised cellular resilience in bipolar disorder (BD) has been associated with structural brain changes and cognitive deficits caused by perturbation of redox status, endoplasmic reticulum (ER) stress and innate immunity. These crucial cellular events are regulated by the ER‑mitochondria close contacts at mitochondria‑associated membranes (MAM) through Ca2+ transfer and lipids exchange between these organelles. The present study aimed to investigate the structural and functional alterations in MAM during BD early stages using patient‑ and control‑derived cellular models, namely dermal fibroblasts. Morphological alterations in close ER‑mitochondria contacts at MAM occur in BD cells and correlate with functional changes, as shown by lipid droplets accumulation. The MAM dysfunction in BD cells parallels changes in Ca2+ homeostasis, namely inhibition of store‑operated Ca2+ entry (SOCE), ER Ca2+ depletion and attenuation of ER‑mitochondria Ca2+ transfer, as well as enhanced ER and oxidative stress and NOD‑like receptor family pyrin domain‑containing 3 (NLRP3) inflammasome activation leading to sterile inflammation. The absence of inflammasome activation upon lipopolysaccharide exposure supports the compromised ability of BD cells (fibroblasts as well as monocytes) to deal with stressful conditions. In conclusion, MAM disruption is highlighted as a potential pathophysiological mechanism driving impaired cellular resilience in BD. Skin fibroblasts are a particularly attractive cellular model for studying mental illnesses, such as BD, due to the shared developmental origin of epidermal and neural tissues. The ectodermal origins of the skin‑brain axis have been proposed as a novel route for understanding brain development, neurodevelopmental conditions and behavior modulation.