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

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $172,800

## Abstract

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 achiev...

## Key facts

- **NIH application ID:** 10138005
- **Project number:** 5K08HL146963-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Kathryn Johnson Gray
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $172,800
- **Award type:** 5
- **Project period:** 2019-04-03 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138005

## Citation

> US National Institutes of Health, RePORTER application 10138005, Signatures of dysfunctional mitochondrial fatty acid oxidation that predispose to early-onset preeclampsia (5K08HL146963-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10138005. Licensed CC0.

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