# The role of MIF in mitochondrial metabolism and M2-TAM polarization

> **NIH NIH F30** · UNIVERSITY OF LOUISVILLE · 2020 · $32,058

## Abstract

PROJECT SUMMARY/ABSTRACT
“The role of MIF in mitochondrial metabolism and M2-TAM polarization.”
 Tumor-associated macrophages (TAMs) promote intratumoral microvessel density, increase tumor
stromal matrix remodeling and potently suppress anti-tumor immunity in late-stage cancer patients. Although
substantial research has identified how “M2” TAM polarization promotes tumor progression, much less is known
about how TAMs obtain this M2 phenotype within tumor microenvironments. Metabolic reprogramming is a
critical determinant of macrophage polarization as recent studies demonstrate that M2 TAMs adopt an oxidative
phosphorylation/mitochondrial metabolic phenotype and uniquely respond to metabolites within the tumor
microenvironment. This proposal’s long-term objective is to investigate the mechanisms by which macrophage
migration inhibitory factor (MIF) dictates lactate-enhanced M2 polarization. Our preliminary studies demonstrate
that M2 macrophages metabolize extracellular lactate to pyruvate which, in turn, is oxidized in the mitochondria
and is both necessary and sufficient to significantly enhancing Th2 cytokine-dependent M2 TAM polarization.
Our data further indicates that MIF promotes mitochondrial metabolism which is required for maximal
lactate/pyruvate-enhanced M2 polarization and acquisition of pro-tumorigenic phenotypes. Two aims are
proposed to test our hypotheses: Specific Aim 1: Delineate the mechanistic effectors of lactate/pyruvate to
HIF1α-dependent M2-macrophage polarization. Objective: To use a combination of metabolic flux analyses,
metabolomics, gene expression assays, transgenic mice and mechanistic studies to answer three primary
questions: 1) Whether M2 macrophages actively metabolize lactate; 2) Which metabolic pathways are utilized
to accomplish this, and; 3) How is lactate metabolism mechanistically linked to M2 polarization Specific Aim 2:
Determine the mechanistic contributions of MIF in lactate/pyruvate-mediated M2 TAM polarization.
Objective: Use mutant MIF protein re-expression, small-molecule rescue studies, flow cytometry and gene
expression assays to make three determinations: 1) Whether MIF dictates mitochondrial biogenesis and
metabolism in M2 macrophages; 2) Whether and how MIF influence mitochondrial metabolism by binding to
CSN5 and regulating NRF2 stability, and; 3) If MIF is functionally linked to lactate-amplified HIF1α stability and
ensuing M2 polarization.

## Key facts

- **NIH application ID:** 9880276
- **Project number:** 5F30CA232550-02
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Jordan T Noe
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,058
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880276

## Citation

> US National Institutes of Health, RePORTER application 9880276, The role of MIF in mitochondrial metabolism and M2-TAM polarization (5F30CA232550-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9880276. Licensed CC0.

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