The major glycerophospholipid phosphatidylethanolamine (PE) in the nervous system is essential for neural development and function. There are two major PE synthesis pathways, the CDP-ethanolamine pathway in the endoplasmic reticulum (ER) and the phosphatidylserine decarboxylase (PSD) pathway in mitochondria. However, the role played by mitochondrial PE synthesis in maintaining cellular PE homeostasis is unknown. Here, we show thatDrosophila pect(phosphoethanolamine cytidylyltransferase) mutants lacking the CDP-ethanolamine pathway, exhibited alterations in phospholipid composition, defective phototransduction, and retinal degeneration. Induction of the PSD pathway fully restored levels and composition of cellular PE, thus rescued the retinal degeneration and defective visual responses inpectmutants. Disrupting lipid exchange between mitochondria and ER blocked the ability of PSD to rescuepectmutant phenotypes. These findings provide direct evidence that the synthesis of PE in mitochondria contributes to cellular PE homeostasis, and suggest the induction of mitochondrial PE synthesis as a promising therapeutic approach for disorders associated with PE deficiency. Author summary Phosphatidylethanolamine (PE) is a critical component of all cellular membranes, and maintaining cellular PE homeostasis is critical for survival and function of cells especially neuronal cells. There are two major PE synthesis pathways in eukaryotes, the CDP-ethanolamine pathway in the endoplasmic reticulum (ER) and the PSD pathway in mitochondria. From a genome-wide genetic screen for genes necessary for photoreceptor cell survival, we identified mutations in the genepect. These mutants displayed defective visual responses, aberrant phospholipid composition, and light-independent retinal degeneration in the absence of mitochondrial defects. Genetic interactions indicated that a deficiency in cellular PE caused retinal degeneration inpectmutants. Strikingly, increasing PE synthesis through the PSD pathway restored levels of cellular PE as well as all PE species, and rescuedpectmutant phenotypes, which is dependent on the exchange of lipids between mitochondria and the ER. Our work provides direct evidence that maintaining cellular PE levels is critical for neuronal function and integrity, suggests that PE synthesized in the mitochondria can be exported to the ER to compensate for deficiencies in cellular PE in neurons, and highlights a fundamental function of mitochondria in cellular phospholipid homeostasis.
