# Evaluating the role of Mecr and Mitochondrial Fatty Acid Synthesis in T cell Function and Metabolism

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $28,169

## Abstract

ABSTRACT
Many inflammatory diseases and cancer are driven by dysregulation of CD4 T helper cells (Th cells). Our group
has shown that different T cell subsets utilize distinct metabolic programs. Proinflammatory Th1 and Th17 T cells
utilize aerobic glycolysis and increase lipid synthesis, while anti-inflammatory T regulatory cells (Tregs) utilize
fatty acid oxidation and oxidative phosphorylation (OXPHOS). Importantly, the lab has shown that manipulation
of metabolic pathways can affect Th cell differentiation, thus offering new approaches to modify immune-related
diseases. Fatty acid and mitochondrial metabolism are critical processes that may be targeted to alter CD4 T
cell fate. Utilizing established in vivo CRISPR screens in models of inflammatory bowel disease and lung
inflammation, I identified several metabolic genes involved in lipid metabolism for this potential purpose. These
screens found mitochondrial fatty acid synthesis (mtFAS) and the mtFAS enzyme Mitochondrial trans-2-enoyl-
coenzyme A reductase (Mecr) to be important in T cell-mediated inflammation. mtFAS is a pathway parallel to
cytosolic fatty acid synthesis that creates acyl-ACP and lipoic acid or longer fatty acid chains crucial for electron
transport chain assembly and OXPHOS. Mecr is the final mtFAS enzyme and humans with MECR loss-of-
function mutations develop a rare neurometabolic disorder. Mechanistically, Mecr-deficient skeletal myoblasts
have reduced OXPHOS and Mecr-knockout in patient fibroblasts and drosophila cause increased levels of iron
and impaired iron-sulfur (Fe-S) cluster biogenesis. Despite cytosolic fatty acid synthesis being well-characterized
in T cells, it is currently unclear what effect Mecr and mtFAS play in immune cells. Therefore, I proposed studying
the effects of Mecr and mitochondrial fatty acid synthesis on T cell function and metabolism. In a Th17 model of
transfer inflammatory bowel disease, Mecr-knockout cells were depleted compared to non-targeting control cells
in the spleens, mesenteric lymph nodes, lamina propria, and intra-epithelial lymphocytes. Mecr-knockout cells
had lower Tbet expression and reduced IFNγ+ T cells, showing reduced Th1 function. In addition, Mecr-knockout
cells had reduced proliferation, increased rates of cell death by apoptosis, and an increase in intracellular iron.
These preliminary data demonstrate that Mecr plays a key role in inflammatory T cells as a rate limiting step in
mtFAS. I hypothesize that mtFAS and Mecr activity supports TCA cycle flux and are required for the
mitochondrial metabolism of Th1 CD4+ T cells. I will utilize control and Mecrfl/fl; Cd4cre conditional knockout
mice that I generated and validated for my experiments in which Mecr will be knocked out specifically in T cells.
I have also developed and utilized single-guide CRISPR/Cas9 knockouts for Mecr and have validated their
functionality. I will: (1) Test the requirement of Mecr expression in the differentiation and function of CD4+ T cells
...

## Key facts

- **NIH application ID:** 10995000
- **Project number:** 1F31DK139660-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** KayLee Kristal Steiner
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $28,169
- **Award type:** 1
- **Project period:** 2024-08-01 → 2025-05-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995000

## Citation

> US National Institutes of Health, RePORTER application 10995000, Evaluating the role of Mecr and Mitochondrial Fatty Acid Synthesis in T cell Function and Metabolism (1F31DK139660-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10995000. Licensed CC0.

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