# Mitochondrial nutrient transport and trophoblast differentiation

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $506,633

## Abstract

PROJECT SUMMARY
Diabetes and obesity in pregnancy cause abnormalities in placental development that underlie adverse
pregnancy outcomes such as spontaneous abortion, preeclampsia, and stillbirth. Central to healthy placental
development is cytotrophoblast differentiation into syncytiotrophoblasts that can be disrupted by diabetes and
obesity by yet unknown mechanisms. Syncytiotrophoblasts facilitate nutrient transport, gas exchange, and
hormone synthesis to support the pregnancy, and their differentiation depends on a highly coordinated
progression of metabolic, epigenetic, and transcriptional reprogramming events. Mitochondrial flux of glucose
and glutamine has emerged as a major factor regulating cellular development, and our initial work shows that
these metabolites play distinctive roles in cellular metabolism and gene expression during trophoblast
differentiation. Glucose primarily fuels citrate and α-ketoglutarate production in rapidly dividing
cytotrophoblasts, while glutamine is the main source in terminally differentiated syncytiotrophoblasts. This shift
is linked to reduced expression of the mitochondrial pyruvate carrier (MPC) in syncytiotrophoblasts, while
mitochondrial glutamine transporter (SLC1A5var) expression remains stable. In this proposal, we will test the
central hypothesis that glucose-derived pyruvate and glutamine flux through the mitochondrial pyruvate
(MPC) and glutamine (SLC1A5var) carriers, respectively, distinctly regulate energetic, epigenetic and
transcriptional reprogramming necessary for trophoblast differentiation. For the proposed experiments, we will
use CRISPR-Cas9 genetic tools to manipulate expression of MPC (Aim 1) or SLC1A5var (Aim 2) in human
trophoblast stem cell (TSC) models. In these lines, we will measure key indices of cellular metabolism using
respirometry and state-of-the-art, high-performance liquid chromatography mass spectrometry (LCMS)-based
quantitative and 13C stable isotope tracing metabolomics methodologies. Moreover, we will examine genome-
wide and locus-specific histone (H3) acetylation and methylation changes through integrative analysis of
CUT&Tag- and RNAseq datasets. Both biochemical and morphologic differentiation will be characterized in
MPC or SLC1A5var loss of function or overexpressing TSCs. Additionally, in parallel experiments we will
employ inhibitors of MPC and glutaminase in primary human trophoblasts to support key findings in TSCs.
Successful completion of study aims will reveal novel, nutrient-responsive mechanisms controlling epigenetic
and transcriptional reprogramming events that are foundational to trophoblast differentiation. Defining these
fundamental pathways is a necessary first step for developing new, evidence-based approaches that fine-tune
placental fuel use and improve placental development and pregnancy outcomes for women with co-morbid
obesity and diabetes.

## Key facts

- **NIH application ID:** 10977578
- **Project number:** 1R01HD113553-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Sarah A Wernimont
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $506,633
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977578

## Citation

> US National Institutes of Health, RePORTER application 10977578, Mitochondrial nutrient transport and trophoblast differentiation (1R01HD113553-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10977578. Licensed CC0.

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