Coenzyme A Restriction as a Factor Underlying Pre-Eclampsia with Polycystic Ovary Syndrome as a Risk Factor

Abstract

Pre-eclampsia is the most common pregnancy complication affecting 1 in 20 pregnancies, characterized by high blood pressure and signs of organ damage, most often to the liver and kidneys. Metabolic network analysis of published lipidomic data points to a shortage of Coenzyme A (CoA). Gene expression profile data reveal alterations to many areas of metabolism and, crucially, to conflicting cellular regulatory mechanisms arising from the overproduction of signalling lipids driven by CoA limitation. Adverse feedback loops appear, forming sphingosine-1-phosphate (a cause of hypertension, hypoxia and inflammation), cytotoxic isoketovaleric acid (inducing acidosis and organ damage) and a thrombogenic lysophosphatidyl serine. These also induce mitochondrial and oxidative stress, leading to untimely apoptosis, which is possibly the cause of CoA restriction. This work provides a molecular basis for the signs of pre-eclampsia, why polycystic ovary syndrome is a risk factor and what might be done to treat and reduce the risk of disease.

Keywords: Coenzyme A; adverse antenatal conditions; genome-wide association study; metabolomics; physiological dysregulation; placenta; polycystic ovary syndrome; pre-eclampsia; systems pathology; transcriptomics.

Figure 1

Common metabolic pathway motif. Pathways represent synthesis of (a) sphingosine-1-P and sphinganine-1-P, (b) oleic and linoleic acids, (c) diacyl glycerol and lysophosphatidyl serine. Rectangles represent enzymes present in human metabolism. Enzyme genes with altered transcript levels are named. Metabolites are in unboxed text, with signaling molecules in bold font. Red and blue colouring respectively denote elevated and reduced levels. Arrows denote products/substrates linking enzymes, except at the start/end of pathways. Enzymes degrading lysophosphatidyl serine (LPCATs) are generally confined to the endoplasmic reticulum. Abbreviations: C16—hexadecanoic acid, CoA—Coenzyme A, FA—fatty acyl, P—phosphate, Sph-1-P—sphingosine-1-phosphate, Sphg-1-P—sphinganine-1-phosphate.

Figure 2

Clinical signs linked to CoA restriction. (a) futile cycle linking to hypoxia and oxidative stress; (b) Sphingosine-1-phosphate cycle linked to hypoxia, hypertension and proteinuria; (c) perturbed valine metabolism effecting thrombogenesis, acidosis and neurotoxicity; (d) central carbon metabolism links acidosis with other conditions. Purple and black boxes respectively represent clinical signs and physiological/biochemical processes, with unboxed nodes corresponding to molecules. Red, blue and black text respectively refer to higher, lower and unchanged activity or molecular concentration. Solid and dashed arrows denote direct and indirect effects or interactions. The barred arrow between PDK4 and PDHA indicates an inhibition event. Abbreviations: 12-KDC—12-Ketodeoxycholate, but—butyric acid, C16—palmitic acid, CoA—Coenzyme A, Ext. PS—External phosphatidylserine, Fas—Fatty acids, LDHB—Lactate Dehydrogenase B, LPL—Lipoprotein Lipase, Lyso-PS—Lysophosphatidyl serine, Mito—mitochondrial, NADH/NAD—ratio of NADH to NAD, PDHA—Pyruvate Dehydrogenase A, PDK4—Pyruvate Dehydrogenase Kinase 4, PNPLA2—Potatin-like phospholipase domain containing 2, PPARa—Peroxisome proliferator-activated receptor alpha, SDSL—Serine/Threonine Dehydratase-like, Sph-1-P—Shingosine-1-phosphate.

Figure 3

Interlinking of separate adverse conditions. Separate adverse cycles could be causing different adverse conditions. However, these come together in PE and the perfect storm of HELLP. Arrows denote links between metabolites, cellular states and disease conditions. The potential link between apoptosis and restricted CoA is represented by a dashed red arrow.