MOTS-c Explained: The Peptide Hidden in Mitochondrial DNA

LynxLab · 24 October 2026 · 8 min read

How Lee and Cohen found MOTS-c inside the mitochondrial 12S rRNA gene in 2015, the AMPK mechanism, and what the 2021 Nature Communications mouse study showed.

Photo: Julian Fernandez, Pexels

Almost every peptide in a research catalogue is coded by a gene in the cell nucleus. MOTS-c is the exception. It is written into the small genome that mitochondria carry around with them, inside a stretch of DNA that textbooks said made ribosomal RNA and nothing else. The story of how mots-c was found, and what it did when injected into mice, is one of the more surprising in recent metabolic research.

A gene hiding inside a ribosomal RNA

Human mitochondrial DNA is a circle of 16,569 base pairs. It carries 13 genes for proteins of the respiratory chain, 2 genes for ribosomal RNAs and 22 for transfer RNAs, as a 2015 commentary in Aging Cell summarised. For decades that was taken as the complete list.

The first crack came in 2001, when a Japanese group found a 24-amino-acid peptide, humanin, coded within the 16S ribosomal RNA gene. If one short open reading frame could hide inside an rRNA gene, others might.

Changhan Lee and Pinchas Cohen at the University of Southern California's Leonard Davis School of Gerontology went looking. They scanned the 12S rRNA gene and found a 51-base-pair reading frame with a strong Kozak sequence, the signal that tells a ribosome where to start translating.

What the 2015 Cell Metabolism paper reported

The result appeared in Cell Metabolism on 3 March 2015 under the title "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance". The name stands for mitochondrial open reading frame of the twelve S rRNA type-c.

The reading frame translates into a 16-amino-acid peptide. Lee and Cohen detected it in multiple tissues of mice and rats, and in the circulating plasma of both rodents and humans. Fasting changed its levels in tissue and in blood, which is the behaviour expected of a metabolic signal rather than a structural fragment.

The paper's summary stated that the primary target organ appeared to be skeletal muscle. For a laboratory ordering mots-c for research, that is the single most useful sentence in the discovery paper, because it defines where the downstream experiments have concentrated.

The folate, AICAR and AMPK mechanism

The mechanism Lee and Cohen proposed is indirect, which is part of why it took time to accept. MOTS-c did not bind a receptor on the cell surface. Inside the cell it inhibited the folate cycle and the de novo purine synthesis pathway tethered to it.

Blocking that pathway caused a metabolite called AICAR to build up. AICAR is a well-known activator of AMP-activated protein kinase, or AMPK, the enzyme that switches cells into an energy-conserving, glucose-burning state when fuel is short. In muscle cells, AMPK activation moved the glucose transporter GLUT4 to the cell membrane and increased glucose uptake.

A second USC paper filled in the next step. In Cell Metabolism in 2018, Kyung Hwa Kim, Lee and colleagues showed that under metabolic stress, such as glucose restriction, MOTS-c moved from the mitochondria into the cell nucleus in an AMPK-dependent manner. There it bound chromatin and regulated a wide set of nuclear genes, including antioxidant response genes controlled by the transcription factor NRF2.

The 2018 finding was the first demonstration of a mitochondrially encoded factor actively controlling nuclear gene expression. It reframed mots c from a metabolic peptide into a messenger between the two genomes in every cell.

What MOTS-c did in mice

The 2015 paper included a series of mouse experiments. In C57BL/6 mice on a high-fat diet with 60% of calories from fat, seven days of MOTS-c at 5 mg/kg/day by intraperitoneal injection improved whole-body insulin sensitivity, measured by the glucose infusion rate during a clamp study.

In outbred CD-1 mice given the same high-fat diet, a lower dose of 0.5 mg/kg/day prevented the development of obesity, and food intake was identical between treated and untreated groups. The same treatment had no effect on body weight in mice eating a normal diet, which argues against a simple appetite or toxicity effect. The paper also reported that MOTS-c prevented the insulin resistance that develops with age in mice.

Levels of two inflammatory signals, IL-6 and TNF-alpha, were also lower in treated animals on the high-fat diet. AMPK activation and GLUT4 expression were confirmed in the skeletal muscle of the treated mice, matching the cell culture work.

The 2021 exercise-mimetic study

The paper that gave MOTS-c its "exercise mimetic" label came six years later. Joseph Reynolds, Lee, Cohen and colleagues published "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis" in Nature Communications on 20 January 2021.

They treated mice at three ages: young at 2 months, middle-aged at 12 months and old at 22 months. Young CD-1 mice given 5 mg/kg/day for two weeks performed better on a rotarod and on an accelerating treadmill. On the treadmill the final stage required a sprint at 23 metres per minute, and every mouse on the higher dose reached it.

The late-life experiment is the one most often quoted. Male C57BL/6N mice were started on intermittent MOTS-c, three times a week at 15 mg/kg, at 23.5 months of age, which the USC team described as the human equivalent of 65 and above. The treated mice showed better grip strength, longer stride length and better performance in a walking test near the end of life, and the authors reported an increase in healthspan.

In the USC press release that accompanied the paper, Lee said the older treated mice "doubled their running capacity on the treadmill" and were able to outrun untreated middle-aged animals. The paper also showed that in cultured C2C12 muscle cells, MOTS-c improved adaptation to metabolic stress in a way that depended on the heat shock factor HSF1.

Anyone evaluating mots-c 10mg vials for a muscle metabolism project should note two limits of the 2021 work. The lifespan data are from male mice only, and the doses used were far above anything tested in humans.

What happens to MOTS-c in exercising humans

The human part of the 2021 study was observational. Sedentary, healthy young men exercised on a stationary bicycle, and the researchers took skeletal muscle biopsies and plasma samples before, during and after the session, and again after a four-hour rest.

Endogenous MOTS-c in muscle rose 11.9-fold after exercise and stayed partly raised after the rest period, with a trend back towards baseline. Plasma levels rose by roughly 50% during and after exercise and returned to baseline after the rest, according to the USC release. Exercise, in other words, is a natural trigger for the peptide.

This is the finding that justifies calling MOTS-c exercise-induced. It does not show that giving the peptide to a person reproduces exercise. No published human trial has tested that, and the only human study of a related compound, discussed in our companion piece on MOTS-c in humans, used a modified analogue rather than the native peptide.

Why WADA banned it and where it stands in the UK

The anti-doping authorities read the mouse papers too. The World Anti-Doping Agency's 2026 Prohibited List, in force from 1 January 2026, names "mitochondrial open reading frame of the 12S rRNA-c (MOTS-c)" explicitly under section S4.4.1, activators of AMPK, alongside AICAR. It is prohibited at all times, in and out of competition.

The United States Anti-Doping Agency's explainer on MOTS-c adds that the peptide is not approved by the FDA for use in humans, and that a therapeutic use exemption is highly unlikely because there is no approved therapeutic use. Any athlete under WADA rules should treat it as banned.

In the UK, MOTS-c has no MHRA marketing authorisation and is supplied for laboratory research only. LynxLab stocks mots-c in the UK for research use in 10mg vials at £24.99, tested to 99% purity with the lab report on the product page. Batch lab reports are published for every product.

For researchers, the attraction is the biology. A 16-residue peptide coded by the mitochondrial genome, activating AMPK through the folate cycle and travelling to the nucleus under stress, is a genuinely new class of signal. Those looking to buy mots-c are buying a tool for studying that signal, with the human questions still open.

Frequently asked questions

What does MOTS-c stand for?

Mitochondrial open reading frame of the twelve S rRNA type-c. It is a 16-amino-acid peptide coded by a 51-base-pair open reading frame inside the mitochondrial 12S ribosomal RNA gene, first described by Changhan Lee and Pinchas Cohen in Cell Metabolism in 2015.

Is MOTS-c an exercise mimetic?

In mice, treatment improved treadmill and rotarod performance at all ages tested, and late-life treatment improved grip strength and gait, in a 2021 Nature Communications study. In humans, exercise raised muscle MOTS-c nearly 12-fold. No human trial has shown that giving the peptide reproduces the effects of exercise.

How does MOTS-c activate AMPK?

It inhibits the folate cycle and de novo purine synthesis inside the cell, causing the metabolite AICAR to accumulate. AICAR activates AMPK, which in muscle cells increases GLUT4 at the membrane and glucose uptake. Under metabolic stress the peptide also moves to the nucleus and regulates gene expression.

Is MOTS-c banned in sport?

Yes. It is named on the WADA 2026 Prohibited List under S4.4.1, activators of AMPK, and is prohibited at all times. USADA notes that a therapeutic use exemption is highly unlikely because there is no approved medical use.

Sources

Research use only

MOTS-C from LynxLab

10mg vials from £24.99. ≥99% purity, lab report on the page. Same-day dispatch, UK stock.

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