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Different CDP-diacylglycerol Synthase (CDS) enzymes participate in the synthesis of cardiolipin in mitochondria and phosphatidylinositol at the endoplasmic reticulum

Blunsom, Nicholas James; (2020) Different CDP-diacylglycerol Synthase (CDS) enzymes participate in the synthesis of cardiolipin in mitochondria and phosphatidylinositol at the endoplasmic reticulum. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Cytidine diphosphate diacylglycerol (CDP-DG) is an essential liponucleotide that is crucial for the synthesis of the phospholipids phosphatidylinositol (PI) and cardiolipin (CL). It is the precursor for PI in the endoplasmic reticulum (ER) and two molecules are required for the synthesis of CL in mitochondria. CDP-DG is formed through the enzymes CDP-DG synthase (CDS) 1 and 2 in the ER; this is the rate-limiting step in the PIP2 cycle. CDS enzymes are critical for the maintenance of cellular structure, as depletion of the CDS enzymes causes a vast array of phenotypes. Upon constant stimulation of phospholipase C via chronic stimulation with arginine-vasopressin in H9c2 cells, there is a specific increase in CDS1 mRNA alongside a decrease in PI levels. PI levels decrease, presumably, due to the increased level of PIP and PIP2 synthesis; CDS1 mRNA increases to attempt to compensate for the drop in PI. This also shows that, contrary to previous studies, CDS1 is responsible for synthesising PI through the products of PIP2 breakdown in the PIP2 cycle, whereas CDS2 is most likely for de novo synthesis of PI. Furthermore, it appears that this increase of CDS1 mRNA due to chronic stimulation with arginine-vasopressin is regulated through protein kinase C and cFos. The two mammalian CDS enzymes are 69% similar and 73% identical, and have been shown to localise to the ER. A novel protein was recently discovered in yeast to have CDS activity which shares very little homology with the CDS enzymes, Tam41, which is a mitochondrial protein. We confirmed that a mammalian version of this enzyme, TAMM41, exists and is responsible for the supply of CDP-DG to the mitochondria for CL synthesis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Different CDP-diacylglycerol Synthase (CDS) enzymes participate in the synthesis of cardiolipin in mitochondria and phosphatidylinositol at the endoplasmic reticulum
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
Keywords: CDP-diacylglycerol synthase, Phosphatidylinositol, Cardiolipin, TAMM41, Mitochondria, Cardiac hypertrophy, Phospholipase C, cFos, Protein kinase C
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10090419
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