Phosphatidylserine synthesis tunes IP₃R-mediated ER Ca²⁺ release via phospholipid homeostasis

Regulation of phospholipid composition is essential for cellular homeostasis. Phosphatidylserine (PS) synthesized in the endoplasmic reticulum (ER) plays critical roles in the plasma membrane and endolysosomal system. Although aberrant PS metabolism is linked to diseases, its cellular effects remain poorly understood. Here, we reveal a conserved role for PS in maintaining Ca²⁺ homeostasis. PS deficiency in Drosophila leads to mitochondrial damage, which is reversed by reducing inositol 1,4,5-trisphosphate receptor (IP₃R)-mediated ER Ca²⁺ release. Notably, in mammalian cells with pathological PS levels-either deficiency or excess as in Lenz-Majewski syndrome-IP₃R activation leads to oscillatory or reduced ER-surface Ca²⁺ release, contrasting with steady-state conditions. Manipulating phospholipid composition via the phosphatidylethanolamine (PE)-SREBP axis in Drosophila and the phosphatidylcholine (PC)-SREBP axis in mammals normalizes IP₃R-mediated Ca²⁺ release during PS deficiency. These findings establish modulated ER Ca²⁺ release as a key function of PS and suggest therapeutic strategies for treating lipid metabolic disorders.