Ca2+ influx through ER-plasma membrane contacts is required for brown fat thermogenesis and metabolic health

This high metabolic activity imposes substantial demands on cellular systems, requiring robust adaptive mechanisms to maintain homeostasis and prevent cellular stress. Yet, the pathways that support and coordinate these adaptive responses in brown adipocytes remain incompletely understood.

Here, we identify a cold- induced adaptive program in BAT characterized by the formation of endoplasmic reticulum- plasma membrane (ER-PM) contact sites and the activation of store-operated calcium entry (SOCE), which is essential for maintaining brown adipocyte health during thermogenic activation. Cold exposure enhances ER-PM contacts and upregulates the expression of STIM and Orai proteins, key mediators of SOCE. Loss of STIM in brown adipocytes disrupts intracellular Ca2+ homeostasis and induces aberrant aggregation of ER membranes.