# Mitochondrial-encoded immunity in restoring macrophage homeostasis under age-related metabolic stress

> **NIH NIH F31** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Age-dependent metabolic dysfunction is associated with maladaptive immune responses. Mitochondria are key
metabolic organelles that are also capable of activating innate immune signaling. Components of the
mitochondria, such as mitochondrial DNA (mtDNA) itself, can trigger immune responses; however, there are
currently no known immunomodulators encoded in the mitochondrial genome. MOTS-c is a peptide encoded in
the mitochondrial genome that we previously characterized as a regulator of metabolic homeostasis during
aging. MOTS-c treatment increases lipid metabolism and prevents diet-induced obesity, fatty liver, and age-
dependent physical decline in mice. Our preliminary data indicate that MOTS-c is induced during monocyte
activation and translocates to the nucleus to regulate gene expression and reprogram the differentiation of
monocytes into macrophages. This suggests that MOTS-c has a crucial role in regulating immune function.
Because MOTS-c regulates responses to metabolic stress and modulates macrophage phenotype, I
hypothesize that MOTS-c will enhance the adaptive capacity of macrophages to maintain homeostasis
during age-related lipid stress. During age- and diet-induced metabolic dysregulation, total cholesterol and
triglyceride levels increase in tissue and in circulation. These lipids can induce maladaptive responses in
monocyte-derived macrophages that promote chronic sterile inflammation. Here, I will test 1) the role of MOTS-
c in preventing maladaptive reprogramming of monocyte-derived macrophages differentiated with lipid stress,
and 2) whether MOTS-c treatment in aged and high-fat diet fed mice prevents macrophage maladaptation and
tissue damage in the liver associated with chronic inflammation. Collectively, these experiments will test the
paradigm-shifting concept that immunity is encoded in both of our co-evolved mitonuclear genomes. This
research, if successful, has broad therapeutic applications in the treatment of age-related chronic inflammatory
diseases.

## Key facts

- **NIH application ID:** 10928108
- **Project number:** 5F31AG082606-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Michelle C Rice
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-08-15 → 2025-08-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928108

## Citation

> US National Institutes of Health, RePORTER application 10928108, Mitochondrial-encoded immunity in restoring macrophage homeostasis under age-related metabolic stress (5F31AG082606-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10928108. Licensed CC0.

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