# Regulation of innate immune cell responses through cell-to-cell transfer of mitochondria

> **NIH NIH DP5** · WASHINGTON UNIVERSITY · 2021 · $393,750

## Abstract

PROJECT SUMMARY
Obesity is an increasingly prevalent metabolic disease that affects 38% of adults and 16% of children and costs
the United States healthcare system nearly $200 billion annually. Consequently, there is an urgent need to better
understand the factors that regulate the development of obesity. Emerging studies indicate that white adipose
tissue (WAT)-resident immune cell populations critically regulate the development of obesity by producing
cytokines that modulate glucose utilization, lipid storage, and energy expenditure. However, despite our
growing understanding of the influence of immune cells on obesity, how metabolic cells such as
adipocytes control immune cell responses remains poorly defined. In preliminary studies, I have identified
that adipocytes transfer their mitochondria to a subset of macrophages in WAT in vivo, potentially defining a new
macrophage population. Strikingly, this process is impaired in high fat diet (HFD)-induced obesity. Further,
mitochondria transplantation to mice results in tissue-specific accumulation of macrophages in WAT and release
of free fatty acids into circulation. These observations suggest that intercellular mitochondria transfer is a
dynamically regulated physiologic process that has important functional effects on lipid metabolism. To dissect
the mechanisms of intercellular mitochondria transfer, I performed a genome-wide CRISPR-knockout screen.
The top-scoring gene, Exostosis 1 (Ext1), is required for heparan sulfate synthesis and is essential for normal
lipid metabolism in mice and humans. Critically, my data indicate that Ext1 is necessary for mitochondria transfer
in vitro without affecting uptake of other foreign bodies. Collectively, these data provoke the central hypothesis
that intercellular transfer of mitochondria from adipocytes to macrophages is a previously unrecognized
mechanism that controls macrophage function and systemic metabolic homeostasis. This hypothesis forms the
basis of my two aims. In Aim 1, I will determine the identity and function of macrophages that have acquired
mitochondria from adipocytes and investigate the immunologic and metabolic potential of these cells. In Aim 2,
I will investigate whether EXT1 is required for intercellular mitochondrial transfer and regulation of metabolic
homeostasis in vivo. These will be addressed employing the intellectual and scientific resources available in the
Brestoff lab, novel strains of mitochondria reporter mice, new genetic models of disrupted mitochondria transfer,
and a suite of metabolism and immunology core facilities at Washington University School of Medicine.
Importantly, these findings may impact how we approach the treatment of metabolic disorders beyond existing
therapeutic paradigms.

## Key facts

- **NIH application ID:** 10247512
- **Project number:** 5DP5OD028125-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jonathan R Brestoff
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2019-09-16 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247512

## Citation

> US National Institutes of Health, RePORTER application 10247512, Regulation of innate immune cell responses through cell-to-cell transfer of mitochondria (5DP5OD028125-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247512. Licensed CC0.

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