Access Type

Open Access Dissertation

Date of Award

January 2014

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

Miriam L. Greenberg

Abstract

Phospholipids are the most abundant lipids in cell membranes. The synthesis of phospholipids is crucial for cellular membrane biogenesis and nearly all aspects of cellular processes. Understanding the regulation of synthesis of phospholipids is beneficial to our fundamental knowledge of cell biology as well as human health.

Regulation of the synthesis of phospholipids is intensively studied in the yeast S. cerevisiae. Most notably, the synthesis of phospholipids is coordinated with the synthesis of inositol, a precursor of inositol-containing lipids, by controlling expression of the genes encoding phospholipid biosynthetic enzymes. In addition to this well-characterized regulatory circuit controlled by the trans-acting factors Ino2, Ino4, and Opi1, this dissertation shows that inositol pyrophosphates are novel regulators of the synthesis of inositol and phosphatidylinositol that control INO1 expression.

Despite the importance of inositol, there are very few reported studies of the

cellular consequences of perturbation of inositol synthesis in human cells.

Studies of SK-N-SH neuronal cells in this dissertation demonstrate that inositol

biosynthesis is essential for cell proliferation and neurite outgrowth, and inhibition of inositol biosynthesis leads to inactivated GSK-3α, which has many regulatory functions in neural systems. This novel finding bridges two prevailing hypotheses of inositol depletion and GSK-3 inhibition and suggests a unifying hypothesis for the therapeutic mechanisms of action of mood-stabilizing drugs.

Although the synthesis of most phospholipids (phosphatidylcholine,

phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol) is

responsive to inositol, the synthesis of cardiolipin (CL) is an exception.

Characterization of the regulation of CL synthesis has unveiled the critical role of CL remodeling via the regulation of the CL-specific phospholipase Cld1.

Transcriptional regulation of Cld1-mediated deacylation of CL influences energy metabolism by modulating the relative contribution of glycolysis and respiration to ATP production. Interestingly, CLD1 expression is responsible for defective growth and respiration in tafazzin-deficient cells. We demonstrate that these underlying defects of tafazzin deficiency are caused by the decreased CL/MLCL ratio, not by a deficiency in unsaturated CL. These findings have significant implications for the life-threatening disorder Barth syndrome.

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