Publications

• Tam41 is a CDP-diacylglycerol synthase required for cardiolipin biosynthesis in mitochondria.

  Tamura Y., Harada Y., Nishikawa S., Yamano K., Kamiya M., Shiota T., Kuroda T., Kuge O., Sesaki H., Imai K., Tomii K., Endo T.

  CDP-diacylglycerol (CDP-DAG) is central to the phospholipid biosynthesis pathways in cells. A prevailing view is that only one CDP-DAG synthase named Cds1 is present in both the endoplasmic reticulum (ER) and mitochondrial inner membrane (IM) and mediates generation of CDP-DAG from phosphatidic ac ... >> More

  CDP-diacylglycerol (CDP-DAG) is central to the phospholipid biosynthesis pathways in cells. A prevailing view is that only one CDP-DAG synthase named Cds1 is present in both the endoplasmic reticulum (ER) and mitochondrial inner membrane (IM) and mediates generation of CDP-DAG from phosphatidic acid (PA) and CTP. However, we demonstrate here by using yeast Saccharomyces cerevisiae as a model organism that Cds1 resides in the ER but not in mitochondria, and that Tam41, a highly conserved mitochondrial maintenance protein, directly catalyzes the formation of CDP-DAG from PA in the mitochondrial IM. We also find that inositol depletion by overexpressing an arrestin-related protein Art5 partially restores the defects of cell growth and CL synthesis in the absence of Tam41. The present findings unveil the missing step of the cardiolipin synthesis pathway in mitochondria as well as the flexibile regulation of phospholipid biosynthesis to respond to compromised CDP-DAG synthesis in mitochondria. << Less

  Cell Metab. 17:709-718(2013) [PubMed] [EuropePMC]

• The CDS1 gene encoding CDP-diacylglycerol synthase in Saccharomyces cerevisiae is essential for cell growth.

  Shen H., Heacock P.N., Clancey C.J., Dowhan W.

  An open reading frame (CDS1) residing on chromosome II of Saccharomyces cerevisiae encodes a hydrophobic protein with a predicted molecular mass of 51,789 Da, which exhibits 29 and 37% amino acid sequence identities with CDP-diacylglycerol synthases reported from Escherichia coli and Drosophila, r ... >> More

  An open reading frame (CDS1) residing on chromosome II of Saccharomyces cerevisiae encodes a hydrophobic protein with a predicted molecular mass of 51,789 Da, which exhibits 29 and 37% amino acid sequence identities with CDP-diacylglycerol synthases reported from Escherichia coli and Drosophila, respectively. Induction of expression of a GAL1 promoter-driven CDS1 gene on a multicopy plasmid in a cds1 null mutant background resulted in synthase activity 10 times that of wild-type cells and an elevation in the apparent initial rate of synthesis of phosphatidylinositol relative to phosphatidylserine. Without induction, activity was reduced to 10% of wild-type levels, which was sufficient to support growth but resulted in an inositol excretion phenotype, and had an opposite effect on the above phospholipid synthesis. Null cds1 mutants were incapable of spore germination or vegetative growth and could not be complemented under uninduced conditions with a GAL1 promoter-driven CDS1 gene on a low copy plasmid. Therefore, the essential CDS1 gene encodes the majority, if not all, of the synthase activity. The lack of consensus RNA splice sites derived from the genomic CDS1 sequence predicts that the multiple subcellular locations for synthase activities do not arise through RNA processing events. << Less

  J. Biol. Chem. 271:789-795(1996) [PubMed] [EuropePMC]

• Mitochondrial CDP-diacylglycerol synthase activity is due to the peripheral protein, TAMM41 and not due to the integral membrane protein, CDP-diacylglycerol synthase 1.

  Blunsom N.J., Gomez-Espinosa E., Ashlin T.G., Cockcroft S.

  CDP diacylglycerol synthase (CDS) catalyses the conversion of phosphatidic acid (PA) to CDP-diacylglycerol, an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PI). CDS activity has been identified in mitochondria and endoplasmic reticulum of m ... >> More

  CDP diacylglycerol synthase (CDS) catalyses the conversion of phosphatidic acid (PA) to CDP-diacylglycerol, an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PI). CDS activity has been identified in mitochondria and endoplasmic reticulum of mammalian cells apparently encoded by two highly-related genes, CDS1 and CDS2. Cardiolipin is exclusively synthesised in mitochondria and recent studies in cardiomyocytes suggest that the peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α and β) serve as transcriptional regulators of mitochondrial biogenesis and up-regulate the transcription of the CDS1 gene. Here we have examined whether CDS1 is responsible for the mitochondrial CDS activity. We report that differentiation of H9c2 cells with retinoic acid towards cardiomyocytes is accompanied by increased expression of mitochondrial proteins, oxygen consumption, and expression of the PA/PI binding protein, PITPNC1, and CDS1 immunoreactivity. Both CDS1 immunoreactivity and CDS activity were found in mitochondria of H9c2 cells as well as in rat heart, liver and brain mitochondria. However, the CDS1 immunoreactivity was traced to a peripheral p55 cross-reactive mitochondrial protein and the mitochondrial CDS activity was due to a peripheral mitochondrial protein, TAMM41, not an integral membrane protein as expected for CDS1. TAMM41 is the mammalian equivalent of the recently identified yeast protein, Tam41. Knockdown of TAMM41 resulted in decreased mitochondrial CDS activity, decreased cardiolipin levels and a decrease in oxygen consumption. We conclude that the CDS activity present in mitochondria is mainly due to TAMM41, which is required for normal mitochondrial function. << Less

  Biochim. Biophys. Acta 1863:284-298(2018) [PubMed] [EuropePMC]