MOTS-c

Mitochondrial ORF of the 12S rRNA type-c

Rank#999
Anti AgingNot ApprovedPhase IIResearchSubQ

Popular for:Exercise mimetic, metabolic health, insulin sensitivity

228

Total Studies

131

Human Studies

Phase II

Evidence Level

Not Approved

FDA Status

Overview

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino-acid peptide encoded in the mitochondrial genome. Discovered in 2015 by Dr. Changhan David Lee at USC, it is the first mitochondrial-derived peptide shown to regulate metabolism at the cellular level. It functions as an exercise mimetic, improving insulin sensitivity, fat metabolism, and exercise capacity.

**Originally developed for: **Research into mitochondrial signaling and aging. MOTS-c was identified during a study of mitochondrial-derived peptides and their role in metabolic regulation. Its potential as an exercise mimetic and anti-aging agent emerged from subsequent research.

Mechanism of Action

MOTS-c activates the AMPK pathway (the master metabolic sensor), which promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. It inhibits the folate-methionine cycle, altering cellular metabolism toward a more active, exercise-like state. It also translocates to the nucleus during metabolic stress to regulate gene expression, particularly genes related to antioxidant response and metabolic homeostasis.

Key Research Benefits

Primary Benefits:

Exercise mimetic — Activates AMPK and mimics the metabolic benefits of exercise (Lee et al., 2015, Cell Metabolism)
Improved insulin sensitivity — Prevents age-related and diet-induced insulin resistance in mice
Fat metabolism — Promotes fatty acid oxidation, reduces fat mass in animal models
Metabolic homeostasis — Regulates glucose uptake and energy expenditure

Secondary/Emerging Benefits:

Anti-aging — Endogenous MOTS-c levels decline with age; supplementation may reverse age-related metabolic decline
Cardiovascular protection — May improve endothelial function and reduce cardiovascular risk markers
Anti-inflammatory — Reduces systemic inflammation markers
Osteoporosis prevention — Animal studies show improved bone density

Clinical Evidence Summary

Research Pipeline

Preclinical
Animal
Phase I
Phase II
Phase III
Approved

228

Total Studies

131

Human Studies

- Lee et al. (2015, Cell Metabolism) — Discovery paper. Demonstrated MOTS-c as a mitochondrial-encoded peptide that regulates insulin sensitivity and metabolic homeostasis via AMPK activation.

- Lee et al. (2019, JACS) — Showed MOTS-c translocates to the nucleus under metabolic stress to regulate adaptive gene expression.

- Reynolds et al. (2021) — MOTS-c levels in human plasma are associated with physical function in aging populations.

- CohBar Phase 1b trial (CB4211) — MOTS-c analog tested at 25 mg/day SubQ in obese patients with fatty liver. Showed improvements in body weight and liver fat.

> Clinical trial status: CB4211 (MOTS-c analog by CohBar) completed Phase 1b. Native MOTS-c has not entered human clinical trials. Research is primarily preclinical (animal models).

Key Studies / PubMed References

228 studies found on PubMed · showing top 25 by relevance

View all on PubMed

MOTS-c in type 2 diabetes mellitus: From risk factors to cardiac complications and potential treatment.

Review

Fang T, Han JC, Taberner A, et al. · Life sciences · 2025

PMID: 41083123

MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes.

In Vitro

Li X, Zhan F, Qiu G, et al. · Redox biology · 2025

PMID: 40403491

MOTS-c: Magical Molecule for Diabetic Cardiomyopathy?

Review

Yerra VG, Connelly KA · Cardiovascular drugs and therapy · 2025

PMID: 40172798

Novel function of MOTS-c in mitochondrial remodelling contributes to its antiviral role during HBV infection.

Human Study

Lin C, Luo L, Xun Z, et al. · Gut · 2024

PMID: 37788894

The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.

Review

Lu H, Fan L, Zhang W, et al. · Cell reports · 2024

PMID: 38206815

Side Effects & Safety

Common Side Effects:

Injection site redness or mild irritation
Mild GI discomfort (nausea, stomach upset)
Transient flushing
Generally well-tolerated in the CB4211 Phase 1b trial

Rare but Serious Risks:

Hypoglycemia risk — MOTS-c improves insulin sensitivity; those on diabetes medications should monitor blood sugar closely
Very limited long-term safety data in humans

> Contraindications: Caution in diabetics on insulin or sulfonylureas (hypoglycemia risk). Not recommended during pregnancy/breastfeeding. Limited interaction data — use caution with other metabolic-altering compounds.

Known Interactions

No curated interaction entry is live for MOTS-c yet.

Until the interaction table is fully populated, use the interaction checker and related peptides below to explore adjacent compounds and likely research pairings.

Frequently Asked Questions

Research Disclaimer

This page is for research and educational purposes only. The information presented is based on published scientific literature and does not constitute medical advice, diagnosis, or treatment recommendations. MOTS-c is not approved by the FDA for human therapeutic use. Always consult a qualified healthcare professional before making any health-related decisions. The studies referenced are linked to their original PubMed sources for verification.