MOTS-c

At a Glance

Molecular Properties

Overview

Compound Description

MOTS-c (Mitochondrial ORF of the 12S rRNA type-c) is a 16-amino-acid mitochondrial-derived peptide encoded within a short open reading frame of the 12S rRNA region of mitochondrial DNA. It is studied as one of a small family of mitochondrial-derived peptides that appear to participate in cellular signaling between mitochondria and the nucleus. This profile summarizes published preclinical and mechanistic research on MOTS-c and is provided strictly for laboratory research and educational reference. It is not a drug, is not intended for diagnosis or treatment, and is not for human or veterinary use.

Mechanism of Action

Research-Identified Pathways

Key Research Findings

Published Study Highlights

• In the foundational 2015 study, MOTS-c was reported to promote AMPK activation and to influence metabolic homeostasis in cell and rodent models, with observations of reduced diet-induced weight gain and insulin resistance in mice.
• Mechanistic research links MOTS-c to the folate–AICAR–AMPK axis, proposing modulation of the one-carbon/folate cycle as an upstream driver of the observed AMPK activation.
• A 2018 study reported that MOTS-c translocates to the nucleus under metabolic stress and regulates stress-responsive nuclear gene expression, including antioxidant-response-element pathways and NRF2 interaction, in an AMPK-dependent manner.
• Preclinical work characterizes MOTS-c as an exercise-induced, mitochondrial-encoded peptide whose expression in skeletal muscle and circulation increased with exercise in the studied models.
• In aged-mouse models, intermittent MOTS-c administration was associated with changes in physical-capacity and muscle-homeostasis endpoints, findings that remain preclinical and not established in humans.

Areas of Research Interest

Why Researchers Are Investigating This Compound

This compound has attracted significant research attention in the following areas. These represent active fields of scientific inquiry, not validated therapeutic claims. No medical benefits are stated or implied.

• Metabolic research: used as a probe to study AMPK signaling, glucose handling, and the folate–AICAR one-carbon cycle in cultured cells and animal models.
• Exercise and mitochondrial biology: investigated as an exercise-responsive mitochondrial-derived peptide in studies of skeletal-muscle energetics and mitochondrial-to-nuclear signaling.
• Aging research: examined in preclinical models for its associations with age-dependent metabolic and physical-capacity endpoints, not as a validated intervention.
• Insulin-sensitivity research: studied as a tool to explore insulin-signaling and metabolic-homeostasis pathways in vitro and in rodent models; these are mechanistic observations, not demonstrated clinical benefits.

Published Research

Peer-Reviewed References

1. Lee C, Zeng J, Drew BG, Sallam T, et al. "The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance." Cell Metabolism (2015). doi:10.1016/j.cmet.2015.02.009
2. Kim KH, Son JM, Benayoun BA, Lee C "The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress." Cell Metabolism (2018). doi:10.1016/j.cmet.2018.06.008
3. Reynolds JC, Lai RW, Woodhead JST, Joly JH, et al. "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis." Nature Communications (2021). doi:10.1038/s41467-020-20790-0
4. Wan W, Zhang L, Lin Y, Rao X, et al. "Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging." Journal of Translational Medicine (2023). doi:10.1186/s12967-023-03885-2