Most of the phosphatidylethanolamine (PE) in mammalian cellsis synthesized by two pathways, the CDP-ethanolamine pathway and the phosphatidylserine (PS) decarboxylation pathway, the final steps of which operate at spatially distinct sites, the endoplasmic reticulum and mitochondria, respectively. We investigated the importance of the mitochondrial pathway for PE synthesis in mice by generating mice lacking PS decarboxylase activity. Disruption of Pisd in mice resulted in lethality between days 8 and 10 of embryonic development. H]ethanolamine was correspondingly increased in hepatocytes. We conclude that the CDPethanolamine pathway in mice cannot substitute for a lack of PS decarboxylase during development. Moreover, elimination of PE production in mitochondria causes fragmented, misshapen mitochondria, an abnormality that likely contributes to the embryonic lethality. Phosphatidylethanolamine (PE)4 is an abundant phospholipid in membranes of organisms ranging from bacteria to mammals. Mammalian cells utilize two major pathways for PE biosynthesis, the CDP-ethanolamine pathway (1) and the phosphatidylserine decarboxylation pathway (2). Most of the ethanolamine that is incorporated into PE is derived from the diet but some is generated by sphingosine-1-phosphate lyase (3). In rat liver/hepatocytes (4, 5) and hamster heart (6) the majority of PE has been reported to originate from the CDP-ethanolamine pathway. In contrast, in cultured Chinese hamster ovary cells (7-9) and baby hamster kidney cells (10), the decarboxylation of phosphatidylserine (PS) produces more than 80% of PE, even when the culture medium is supplemented with ethanolamine, an obligatory substrate of the CDP-ethanolamine pathway. Many types of mammalian cells grow and divide normally when cultured in the absence of ethanolamine, suggesting that PE production from the CDP-ethanolamine pathway might not be not essential for cell growth (10), although it is likely that the relative importance of the two pathways of PE synthesis depends on the type of cell and tissue. In Escherichia coli, in which PE comprises ϳ75% of total phospholipids, all PE is derived from PS decarboxylase. Interestingly, E. coli that have been genetically manipulated to reduce the PE content to 0.007% of total phospholipids are viable when supplemented with divalent cations such as Mg 2ϩ and Ca 2ϩ (11, 12). The two major pathways for PE synthesis in mammalian cells operate in different subcellular compartments. The final reaction of the CDPethanolamine pathway, catalyzed by CDP-ethanolamine:1,2-diacylglycerol ethanolaminephosphotransferase, occurs primarily on endoplasmic reticulum (ER) and nuclear membranes (13, 14), whereas PS decarboxylase activity is restricted to the outer surface of mitochondrial inner membranes (15, 16). Thus, the potential exists for compartmentalization of PE pools originating from these two spatially segregated pathways. Indeed, in Chinese hamster ovary cells and in yeast, the majority of mitochondrial PE is synthesized within mitochondria by PS decar...

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