MOTS-c
A peptide encoded by mitochondrial DNA that signals back to the nucleus.
Mitochondrial & energy · 7 min read · updated 13 Aug 2026
Research use only. The ranges below are what published studies and community protocols report. They are reference material for laboratory research, not medical advice or a recommendation for human or veterinary use.
The compound
MOTS-c
View- Type
- Mitochondrial-Derived Peptide
- CAS
- N/A
- Formula
- C₁₀₂H₁Base150N₂₈O₂₃S
- Mass
- ~2174 Da
At a glance
- Class
- Mitochondrial-derived peptide (MDP)
- Sequence
- MRWQEMGYIFYPRKLR — 16 amino acids
- Encoded by
- Mitochondrial 12S rRNA open reading frame
- Molecular weight
- ~2174 Da
- Native half-life
- Short — minutes to roughly an hour
- Vial sizes stocked
- 10 mg, 20 mg, 40 mg
MOTS-c is short for "mitochondrial open reading frame of the 12S rRNA type-c". It is one of a small family of peptides that are not encoded in the nucleus at all — the gene sits inside mitochondrial DNA. That matters conceptually: mitochondria are usually described as receiving instructions from the nucleus, and MOTS-c is evidence of traffic running the other way.
Under metabolic stress the peptide translocates from the mitochondrion into the nucleus, where it associates with stress-responsive transcription factors and influences nuclear gene expression — antioxidant response elements in particular. This retrograde signalling is the mechanism that earned it the "exercise mimetic" description, because the transcriptional programme it engages overlaps substantially with the one exercise engages.
Circulating MOTS-c declines with age and is acutely elevated by exercise in human plasma. The age-related decline comes from the original characterisation work; the exercise-induced rise in human muscle and plasma was reported later by Reynolds et al. (Nature Communications, 2021). Together they are the main reason the peptide attracted research interest beyond its molecular novelty.
Mechanism in detail
The best-described route runs through one-carbon metabolism. MOTS-c interferes with the folate–methionine cycle, causing the purine intermediate AICAR to accumulate. AICAR is an endogenous AMPK activator, so the downstream consequence is AMPK activation without a change in cellular AMP:ATP ratio.
- AMPK activation shifts substrate preference toward fatty-acid oxidation and glucose uptake and away from lipogenesis.
- Skeletal muscle: improved insulin sensitivity and glucose disposal in rodent models, including in diet-induced insulin-resistant animals.
- Nuclear translocation: under glucose restriction or oxidative stress MOTS-c enters the nucleus and co-regulates ARE-driven genes alongside NRF2, expanding the antioxidant response.
- Adipose tissue: reduced fat accumulation in rodent models fed a high-fat diet, without a matching reduction in food intake — an expenditure-side rather than intake-side effect.
Where the evidence actually stands
Be clear-eyed about this one. The mechanistic and rodent literature is genuine and well-cited; the controlled human interventional literature is very thin. Human data mostly consists of observational plasma measurements — MOTS-c falls with age, rises with acute exercise, and differs between metabolically healthy and unhealthy cohorts. Those are associations, not demonstrations that administering the peptide reproduces the phenotype.
Protocol ranges in circulation are therefore derived from rodent dosing and community practice rather than from dose-finding trials. Treat them as starting points for research design, not as validated regimens.
Storage
- Lyophilised: 2–8 °C short term, −20 °C for extended storage, protected from light.
- Reconstituted: 2–8 °C, used within about 28 days. Do not freeze reconstituted material.
- The 40 mg vial is the one most likely to expire before it empties. Reconstitute the volume you will actually use.
Cautions
- Human safety data are minimal. There is no established adverse-event profile because there are no controlled dosing trials of any size.
- Effects on glucose disposal are the most reproducible finding in animal work; any model with concurrent glucose-lowering interventions should account for additivity.
- Injection-site reactions are the most commonly reported practical issue.
References & credit
- 1Lee C et al., Cell Metabolism 2015 — Original identification of MOTS-c and the folate cycle / AICAR / AMPK mechanism.
- 2Reynolds JC et al., Nature Communications 2021 — MOTS-c, exercise adaptation and age-dependent effects in mice.
- 3Kim KH et al., Cell Metabolism 2018 — Nuclear translocation and adaptive nuclear gene regulation under metabolic stress.
This article was written in-house. Where a dose range reflects community practice rather than a published trial, the community references we consulted are credited above and the article says which is which.