# Novel Regulators of Aging Metabolism Encoded in the Mitochondrial Genome

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $338,250

## Abstract

   
DESCRIPTION (provided by applicant): Mitochondria not only serve as the major source of cellular energy, but also as a coordinator of the highly sophisticated metabolic system. Coordination requires communication, and thus our long-term interest is in how mitochondria transmit messages to regulate metabolic homeostasis. Mitochondrial signaling has emerged as a key regulator of aging, but signals that have been described to date are not encoded in the mitochondrial genome. The identification of Humanin, a peptide encoded in the mitochondrial DNA, provided a paradigm-shifting regulatory mechanism of mitochondrial communication. We have recently discovered a novel peptide encoded within the mitochondrial DNA and named it MOTS-c (Mitochondrial ORF within the Twelve S rRNA). MOTS-c acts on the skeletal muscle and promotes cellular glucose and fatty acid metabolism, mediated by the folate-AMPK pathway. In mice, MOTS-c regulates glucose homeostasis and prevents obesity and insulin-resistance in high-fat fed young mice. We have also obtained evidence supporting MOTS-c-dependent regulation of metabolic aging: (i) MOTS-c levels in mice decline with age in circulation and skeletal muscle concomitantly with the development of muscle insulin-resistance and (ii) systemic injection of MOTS-c for a week sufficiently reversed age-dependent muscle insulin resistance. We hypothesize that MOTS-c is a mitochondrial-encoded regulator of the folate-AMPK pathway that promotes metabolic homeostasis and that restoring the age-dependent decline of MOTS-c can reverse metabolic aging. We propose to study (i) the impact of aging on MOTS-c biology and conversely (ii) the effect of MOTS- c on aging metabolism. We will take a top-down approach with 3 aims to test our hypothesis. Aim 1 will determine the age-dependent impact of MOTS-c on metabolic aging in mice. Aim 2 will examine the role of MOTS-c in regulating cellular metabolism in young vs aged primary muscle cells. Aim 3 will test the folate- AMPK pathway in mediating MOTS-c-dependent metabolism during aging. These findings will add an entirely novel 'mitochondrial-centric' mechanistic layer to the regulation of aging metabolism, and provide a new therapeutic target for age-dependent metabolic conditions.

## Key facts

- **NIH application ID:** 9923533
- **Project number:** 5R01AG052558-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Changhan Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,250
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923533

## Citation

> US National Institutes of Health, RePORTER application 9923533, Novel Regulators of Aging Metabolism Encoded in the Mitochondrial Genome (5R01AG052558-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9923533. Licensed CC0.

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