Signatures of dysfunctional mitochondrial fatty acid oxidation that predispose to early-onset preeclampsia

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Preeclampsia (PE), the development of new-onset hypertension and proteinuria after 20 weeks gestation, is a severe pregnancy-specific disorder mediated by the placenta that affects 5% of all pregnancies. The clinical features of PE are caused by diffuse maternal endothelial cell dysfunction, mediated by an imbalance of circulating anti-angiogenic factors in the maternal blood (i.e., sFlt1, PlGF). Women with prior PE have an increased lifetime risk of cardiovascular disease. The underlying etiology of PE remains poorly understood; consequently, predictive and therapeutic options remain limited and delivery is the only cure. In a variant form of PE, acute fatty liver of pregnancy (AFLP), an increased proportion of fetuses are affected by the autosomal recessive fatty acid oxidation disorder, LCHAD (long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency) caused by mutations in the HADHA gene. AFLP may result from the build-up of long-chain and 3-hydroxy long- chain fatty acids in the placenta, which are then transported into the maternal circulation and lead to maternal liver toxicity. Based on the hypothesis that underlying metabolic changes may underlie disposition to PE in many women, we recently performed global metabolic profiling on 1st and 2nd trimester plasma samples from women who developed early-onset PE (EO-PE, delivered <37 weeks) and matched controls. In this cohort, EO-PE cases had evidence of early abnormal mitochondrial fatty acid β-oxidation (β-FAO), characterized by increased plasma medium- and long-chain fatty acids, acylcarnitines, and ketones. These data implicate dysfunctional β-FAO by the mitochondria as an early step in PE pathogenesis. Here we propose a series of experiments to understand why β-FAO is dysregulated in PE and test the effects of abnormal β-FAO on mitochondrial function in the placenta and maternal vasculature. Our central hypothesis is that dysfunctional mitochondrial fatty acid β- oxidation in the placenta beginning in early pregnancy is a critical mediator of PE pathogenesis. To test this hypothesis, we will: (1) delineate the level at which abnormal fatty acid β-oxidation originates in PE by examining β-FAO-associated genetic variants, gene expression, and metabolites in maternal and fetal/placental pregnancy samples, and (2) characterize the functional effects of elevated β-FAO-related metabolites on mitochondria in cell types integral in PE pathogenesis (i.e., placental trophoblasts and maternal vascular endothelium). Together, these aims will define the molecular basis for dysregulated β-FAO in women who develop PE and determine the specific effects of FAO-related metabolites on mitochondrial function in trophoblasts and vascular endothelium. We anticipate these experiments will significantly deepen our knowledge of PE pathogenesis, ultimately leading to improved predictive and therapeutic options for PE. Additionally, the training I will receive during this career award will be essential for me to achieve my long-term goal of developing an independent research program based in translating results of integrative `omic analyses in patients into functional follow-up to understand mechanisms underlying adverse obstetric outcomes.