Regulation of Cardiolipin Biosynthesis in H9c2 Cardiac Myoblasts by Cytidine 5'-Triphosphate

doi:10.1074/jbc.271.42.25810

Volume 271, Number 42, Issue of October 18, 1996 pp. 25810-25816
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of Cardiolipin Biosynthesis in H9c2 Cardiac Myoblasts by Cytidine 5 $'$ -Triphosphate

(Received for publication, June 12, 1996, and in revised form, July 1, 1996)

Grant M. Hatch and Grant McClarty

From the Departments of Pharmacology and Therapeutics, Biochemistry and Molecular Biology, Internal Medicine and Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E OW3, Canada

The regulation of cardiolipin biosynthesis by CTP in H9c2 cardiac myoblasts was investigated. H9c2 cells were incubated in the presence of cyclopentenylcytosine which is converted to cyclopentenylcytosine-triphosphate, a potent and specific inhibitor of CTP synthetase. Incubation of cells for 12 h with cyclopentenylcytosine reduced the cellular pool size of CTP to less than 10% of control cells but did not influence the pool size of other nucleotides. The de novo biosynthesis of phosphatidylcholine from [methyl-³H]choline, phosphatidylethanolamine from [1-³H]ethanolamine, and biosynthesis of all glycerol containing phospholipids from [U-¹⁴C]glycerol or [1,3-³H]glycerol were reduced approximately 50% after preincubation of the cells with cyclopentenylcytosine. In contrast, radioactive glycerol accumulated in phosphatidic acid, diacylglycerol, and triacylglycerol in cyclopentenylcytosine-treated cells compared with controls suggesting a re-routing of phospholipid biosynthesis away from CTP utilizing reactions toward neutral lipid synthesis. The de novo biosynthesis of all phospholipids was restored to control levels by addition of cytidine to the medium which elevated CTP levels. Cyclopentenylcytosine did not affect the in vitro enzyme activities involved in cardiolipin biosynthesis in these cells. In addition, the resynthesis of cardiolipin and most phospholipids from [1-¹⁴C]linoleic acid was not affected by cyclopentenylcytosine. Our findings indicate that the cellular CTP level may regulate cardiolipin biosynthesis in H9c2 cardiac myoblasts and support the notion that the cellular CTP level may be a universal signal/switch for all phospholipid biosynthesis in eukaryotic cells.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

G. M. Hatch, Y. Gu, F. Y. Xu, J. Cizeau, S. Neumann, J.-S. Park, S. Loewen, and M. R.A. Mowat
StARD13(Dlc-2) RhoGap Mediates Ceramide Activation of Phosphatidylglycerolphosphate Synthase and Drug Response in Chinese Hamster Ovary Cells
Mol. Biol. Cell, March 1, 2008; 19(3): 1083 - 1092.
[Abstract] [Full Text] [PDF]

M. J. Higgins, P. R. Graves, and L. M. Graves
Regulation of Human Cytidine Triphosphate Synthetase 1 by Glycogen Synthase Kinase 3
J. Biol. Chem., October 5, 2007; 282(40): 29493 - 29503.
[Abstract] [Full Text] [PDF]

Y.-F. Chang, S. S. Martin, E. P. Baldwin, and G. M. Carman
Phosphorylation of Human CTP Synthetase 1 by Protein Kinase C: IDENTIFICATION OF Ser462 AND Thr455 AS MAJOR SITES OF PHOSPHORYLATION
J. Biol. Chem., June 15, 2007; 282(24): 17613 - 17622.
[Abstract] [Full Text] [PDF]

M.-G. Choi and G. M. Carman
Phosphorylation of Human CTP Synthetase 1 by Protein Kinase A: IDENTIFICATION OF Thr455 AS A MAJOR SITE OF PHOSPHORYLATION
J. Biol. Chem., February 23, 2007; 282(8): 5367 - 5377.
[Abstract] [Full Text] [PDF]

A. J. Chicco and G. C. Sparagna
Role of cardiolipin alterations in mitochondrial dysfunction and disease
Am J Physiol Cell Physiol, January 1, 2007; 292(1): C33 - C44.
[Abstract] [Full Text] [PDF]

G.-S. Han, A. Sreenivas, M.-G. Choi, Y.-F. Chang, S. S. Martin, E. P. Baldwin, and G. M. Carman
Expression of Human CTP Synthetase in Saccharomyces cerevisiae Reveals Phosphorylation by Protein Kinase A
J. Biol. Chem., November 18, 2005; 280(46): 38328 - 38336.
[Abstract] [Full Text] [PDF]

Y. J. Jiang, B. Lu, F. Y. Xu, J. Gartshore, W. A. Taylor, A. J. Halayko, F. J. Gonzalez, J. Takasaki, P. C. Choy, and G. M. Hatch
Stimulation of cardiac cardiolipin biosynthesis by PPAR{alpha} activation
J. Lipid Res., February 1, 2004; 45(2): 244 - 252.
[Abstract] [Full Text] [PDF]

M.-G. Choi, T.-S. Park, and G. M. Carman
Phosphorylation of Saccharomyces cerevisiae CTP Synthetase at Ser424 by Protein Kinases A and C Regulates Phosphatidylcholine Synthesis by the CDP-choline Pathway
J. Biol. Chem., June 20, 2003; 278(26): 23610 - 23616.
[Abstract] [Full Text] [PDF]

F. Y. Xu, W. A. Taylor, J. A. Hurd, and G. M. Hatch
Etomoxir mediates differential metabolic channeling of fatty acid and glycerol precursors into cardiolipin in H9c2 cells
J. Lipid Res., February 1, 2003; 44(2): 415 - 423.
[Abstract] [Full Text] [PDF]

G. M. Hatch, A. J. Smith, F. Y. Xu, A. M. Hall, and D. A. Bernlohr
FATP1 channels exogenous FA into 1,2,3-triacyl-sn-glycerol and down-regulates sphingomyelin and cholesterol metabolism in growing 293 cells
J. Lipid Res., September 1, 2002; 43(9): 1380 - 1389.
[Abstract] [Full Text] [PDF]

B. J. Ma, W. A. Taylor, V. W. Dolinsky, and G. M. Hatch
Acylation of monolysocardiolipin in rat heart
J. Lipid Res., October 1, 1999; 40(10): 1837 - 1845.
[Abstract] [Full Text]

A. Pappas, W.-L. Yang, T.-S. Park, and G. M. Carman
Nucleotide-dependent Tetramerization of CTP Synthetase from Saccharomyces cerevisiae
J. Biol. Chem., June 26, 1998; 273(26): 15954 - 15960.
[Abstract] [Full Text] [PDF]

S. F. O'Handley, C. A. Dunn, and M. J. Bessman
Orf135 from Escherichia coli Is a Nudix Hydrolase Specific for CTP, dCTP, and 5-Methyl-dCTP
J. Biol. Chem., February 16, 2001; 276(8): 5421 - 5426.
[Abstract] [Full Text] [PDF]