Phosphatidylethanolamine

KEY FACTS:

PE is the second most abundant phospholipid and precursor to phosphatidylcholine (PC)

CDP-Etn Kennedy pathway converts diacylglycerol (DAG) and Etn to PE de novo via 3 genes: Etn Kinase (EK), CTP:phosphoethanolamine cytidyltransferase (ECT), and CDP-Etn:1,2-DAG Etn phosphotransferase (EPT)

Nuclear encoded mitochondrial Psd1/PSD decarboxylates phosphatidylserine (PS) into PE in the inner mitochondrial membrane, subsequently transporting some Psd1-derived PE to the ER for PC synthesis

Two minor PE synthesis pathways: Lyso-PE and head group base exchange.

Psd1 substrate, PS is synthesized in mitochondrial-associated membranes for easy membrane lipid flux.

Preferential mitochondrial import of unsaturated PS results in variance among PE species produced by the Kennedy and PSD pathways

METABOLIC ROLE:

PE provides P-Etn to GPI anchor precursors via lipid transfer proteins

PE can be variously modified including ubiquitin and Atg8 conjugation, which facilitates intra-luminal vesicle and autophagosome formation, respectively

Ferroptosis induction via accumulation of reactive oxygen species results in PE oxidation and leaflet flipping

Disruption of the CDP-Etn pathway via ECT or EPT mutations cause hereditary spastic paraplegia

Mutations in PISD can result in mitochondrial diseases such as Liberfarb Syndrome, characterized by a 50% reduction in mitochondrial PE synthesis

PE is vital for normal cristae structure and has a conserved functionally important interaction with complex III

Phosphatidylethanolamine (PE), the second most abundant phospholipid, representing 15-25% of total cellular lipids, preferentially localizes to the plasma membrane inner leaflet. PE synthesis occurs via two major routes, the CDP-Ethanolamine (Etn) Kennedy pathway in the endoplasmic reticulum (ER) and via phosphatidylserine decarboxylase (Psd1/PISD) in the inner mitochondrial membrane (IMM). Suggestive of dual requirement, total loss of either major PE synthesis pathway is embryonically lethal in mammals.

Inducing negative curvature, PE aids in cellular membrane dynamics including fissions, fusions, and mitochondrial cristae structure. PE’s involvement also extends to autophagy, mitophagy, and ferroptosis via protein conjugation or oxidation. Cells deficient in Psd1/PISD consistently exhibit decreased respiratory capacity and ATP production and increased mitochondrial derived compartments and fragmentation. Disruptions in either pathway can thus result in pathological neuronal states.