# Cytokine-mediated reprogramming of mitochondrial function

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $390,000

## Abstract

ABSTRACT
 Mitochondria are metabolic organelles that are essential not only for energy transduction, but also a range
of other functions including biosynthesis, ion and metal homeostasis, and signaling. The long-term goal of our
laboratory is to better understand how mitochondrial function can adjust cell physiology and fate. A hallmark
example of how mitochondria can be repurposed to adjust cell function is observed in macrophages, cells of the
innate immune system. Upon activation of pro-inflammatory programs, such as with the bacterial membrane
component lipopolysaccharide, rates of mitochondrial ATP production steeply collapse, as mitochondria are
reprogrammed to generate signals that amplify the innate immune response.
 However, many of the same pathways engaged in macrophages during inflammatory activation [e.g. toll-
like receptor (TLR) and interferon signaling] are also widely present in many other cell types. While this cytokine-
mediated mitochondrial reprograming may be evolutionarily beneficial for host defense, these pathways may be
damaging when engaged in non-immune cells, particularly electrically excitable cells hugely reliant on oxidative
phosphorylation. Moreover, deleterious cytokine-driven effects on mitochondrial energetics could explain why
metabolic dysfunction and low-grade inflammation are coincident in a range of chronic and age-related diseases.
 Over the next five years, we propose to thoroughly and mechanistically characterize how common
cytokine-linked pathways – such as TLR and interferon signaling – rewire mitochondria in a range of cell types.
We will define the broader transcriptional programs required for this mitochondrial remodeling using
pharmacologic and genetic mouse models. Additionally, the proposal will examine how cytokine-driven changes
in core mitochondrial processes (e.g. oxidative phosphorylation, biosynthetic pathways, retrograde signaling,
etc.) manifest in altered physiology in cells and ex vivo organoids. By purposefully and systematically defining
how cytokines reprogram mitochondrial metabolism, this interdisciplinary program promises to reveal new
insights into mitochondrial adaptations to stress as well as crosstalk between metabolism and inflammation.
Moreover, efforts to pinpoint the regulatory enzymes and pathways driving these changes can help guide novel
therapeutic approaches seeking to restore mitochondrial function in the array of diseases that are associated
with enhanced inflammation and rooted in metabolic dysfunction.

## Key facts

- **NIH application ID:** 10862590
- **Project number:** 5R35GM138003-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Ajit Divakaruni
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862590

## Citation

> US National Institutes of Health, RePORTER application 10862590, Cytokine-mediated reprogramming of mitochondrial function (5R35GM138003-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10862590. Licensed CC0.

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