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Papers In Press, published online ahead of print September 28, 2005
Department of Medicine, University of Alberta, Edmonton, AB T6G 2S2
Corresponding Author: jean.vance{at}ualberta.ca
Most of the phosphatidylethanolamine (PE) in mammalian cells is 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. Electron microscopy of Pisd–/– embryos revealed large numbers of aberrantly shaped mitochondria. In addition, fluorescence confocal microscopy of Pisd–/– embryonic fibroblasts showed fragmented mitochondria. PS decarboxylase activity and mRNA levels in Pisd+/– tissues were approximately one-half of those in wild-type mice. However, heterozygous mice appeared normal, exhibited normal vitality, and the phospholipid composition of their livers, testes, brains, and of mitochondria isolated from livers, was the same as in wild-type littermates. The amount and activity of a key enzyme of the CDP-ethanolamine pathway for PE synthesis, CTP:phosphoethanolamine cytidylyltransferase, were increased by 35– 40% and 100%, respectively, in tissues of Pisd+/– mice, as judged by immunoblotting; PE synthesis from [3H]ethanolamine was corespondingly increased in hepatocytes. We conclude that the CDP-ethanolamine 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.
J. Biol. Chem, 10.1074/jbc.M506510200
Submitted on June 15, 2005
Accepted on September 28, 2005
Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects
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