Phosphatidylserine synthase regulates cellular homeostasis through distinct metabolic mechanisms

Phosphatidylserine (PS), synthesized in the endoplasmic reticulum (ER) by phosphatidylserine synthase (PSS), is transported to the plasma membrane (PM) and mitochondria through distinct routes. The in vivo functions of PS at different subcellular locations and the coordination between different PS transport routes are not fully understood. Here, we report that Drosophila PSS regulates cell growth, lipid storage and mitochondrial function. In pss RNAi, reduced PS depletes plasma membrane Akt, contributing to cell growth defects; the metabolic shift from phospholipid synthesis to neutral lipid synthesis results in ectopic lipid accumulation; and the reduction of mitochondrial PS impairs mitochondrial protein import and mitochondrial integrity. Importantly, reducing PS transport from the ER to PM by loss of PI4KIIIα partially rescues the mitochondrial defects of pss RNAi. Together, our results uncover a balance between different PS transport routes and reveal that PSS regulates cellular homeostasis through distinct metabolic mechanisms.
Author summary Phosphatidylserine (PS), a membrane phospholipid synthesized in the endoplasmic reticulum (ER) by the enzyme phosphatidylserine synthase (PSS), is transported to the plasma membrane (PM) and mitochondria through different paths. The cellular functions of PS at different places in the cell and the mechanisms that coordinate the different PS transport paths are not fully understood. Here, we identified that PSS regulates cell growth, lipid storage and mitochondrial function in the fruit fly larval salivary gland. We showed that loss of pss function has three effects: (1) reduced levels of PS lead to reduced levels of plasma membrane Akt, a key component in the insulin pathway, which is important for cell growth; (2) it causes a shift from phospholipid synthesis to neutral lipid synthesis, which results in excess lipid accumulation; and (3) it reduces the level of mitochondrial PS, which impairs mitochondrial protein import and mitochondrial morphology. We also found that reducing the transport of PS from the ER to PM partially rescues the mitochondrial defects caused by loss of pss function. Together, our results reveal that PSS regulates cellular homeostasis through distinct metabolic changes, and uncover a balance between different PS transport pathways.