Peptide of the Week: MOTS-c, the Mitochondrial Peptide

MOTS-c is often described as an "exercise mimetic" or a longevity peptide. The research behind it is genuinely interesting: it is one of a small number of peptides encoded not in the cell's nucleus but in its mitochondria.

It is also very early-stage. This week we cover how MOTS-c was discovered, what it does in mice, what has been measured in people, and the gap that matters most: the absence of human treatment trials.

A peptide encoded by mitochondria

Mitochondria are the structures inside cells that produce most of their usable energy. They carry their own small genome, separate from the DNA in the nucleus.

In 2015, researchers reported a short open reading frame (a stretch of DNA that can be read to make a protein) hidden inside the mitochondrial 12S rRNA gene. It encodes a 16-amino-acid peptide they named MOTS-c, short for "mitochondrial open reading frame of the 12S rRNA-c" (Lee 2015).

MOTS-c belongs to a group called mitochondrial-derived peptides. An earlier mitochondrial-derived peptide, humanin, prompted the search that led to MOTS-c (Lee 2015). A review has described MOTS-c moving to the cell nucleus during metabolic stress, where it influences the activity of nuclear genes (Zheng 2023).

What the animal studies found

Metabolism and AMPK

The discovery paper found that MOTS-c's main target appeared to be skeletal muscle. In cells, it inhibited the folate cycle and a linked pathway for making purines (building blocks of DNA), which led to activation of AMPK (Lee 2015). AMPK is an enzyme that acts as a cellular energy sensor. When energy runs low, it shifts cells toward taking up and burning fuel.

In mice, MOTS-c treatment prevented both age-related and high-fat-diet-induced insulin resistance, as well as diet-induced obesity (Lee 2015).

Physical performance and aging

A 2021 study from the same senior author found that MOTS-c improved physical performance in young, middle-aged and old mice. When intermittent treatment (three times a week) was started very late in life, at 23.5 months, it increased physical capacity and healthspan in mice (Reynolds 2021).

These are mouse results. Findings in mice, especially on metabolism and lifespan, frequently fail to carry over to people. That makes MOTS-c firmly preclinical as a treatment. Two authors on both papers reported being consultants and shareholders of CohBar, Inc. (Reynolds 2021).

What has been measured in humans

Human research on MOTS-c so far is observational: scientists measure the body's own MOTS-c in blood or muscle and look for associations. Nobody in these studies was given MOTS-c.

Exercise. The 2021 study above also reported that exercise raised the body's own MOTS-c in skeletal muscle and in circulation (Reynolds 2021). A separate randomized study of 30 people found MOTS-c showed only a trend toward an increase after a single endurance session, while humanin rose significantly. Plasma levels of these peptides were not related to fitness (von Walden 2021).

Age. In healthy men, circulating MOTS-c was lower with age. Yet muscle MOTS-c was about 1.5-fold higher in middle-aged and older men than in young men (D'Souza 2020). Blood and muscle levels, in other words, did not move together.

Metabolic health. Here the findings point in different directions:

• In 125 Chinese adults without diabetes, plasma MOTS-c was higher in those with metabolic syndrome and was linked most strongly to waist circumference and liver fat (Sequeira 2021).
• In a Turkish study of 85 adults, serum MOTS-c did not differ between people with obesity and those of normal weight. Levels rose with insulin resistance and fell with age (Ozkaya 2025).

The average levels reported in those two studies differ by more than twentyfold (about 315 pg/mL versus about 14 pg/mL). Different populations and measurement methods make human MOTS-c data hard to compare across studies.

What these studies cannot tell you is cause and effect. Higher MOTS-c alongside more liver fat could reflect the body responding to metabolic stress, which is what the Sequeira authors proposed. It does not show that raising MOTS-c from outside would help.

The missing piece: human treatment trials

We searched PubMed for clinical trials in which people were given MOTS-c. Every randomized trial we found that mentioned MOTS-c used it as a measurement, for example tracking blood levels during exercise or other treatments. We found no published human interventional trial of MOTS-c itself, whether for safety, dosing or efficacy.

A 2023 review reached a similar conclusion, noting that no effective method of applying MOTS-c in the clinic had been developed (Zheng 2023).

That means there is no published human data on MOTS-c's safety, half-life or side effects when given as a drug. Any dose discussed online is not based on human trial data.

How it compares

MOTS-c is often grouped with other mitochondria-focused compounds, but they are very different:

• SS-31 (elamipretide) is a synthetic, lab-designed peptide rather than one the body makes, with a different mechanism and a separate research history. See MOTS-c vs SS-31.
• Humanin is MOTS-c's closest relative, and the two are sold together as a MOTS-c / Humanin blend.
• AICAR is another compound often discussed in the same AMPK context.

MOTS-c also appears in the Epitalon + NAD+ + MOTS-c stack. We found no published trials of that combination.

The bottom line

MOTS-c is a real discovery about how mitochondria may signal to the rest of the body, and the mouse data on insulin sensitivity and physical capacity are striking. The human data are observational, sometimes contradictory, and say nothing about what happens when MOTS-c is given as a treatment. Until human trials exist, its effects in people are unknown.

Sources

• The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab, 2015. PMID 25738459
• MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol (Lausanne), 2023. PMID 36761202
• MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun, 2021. PMID 33473109
• Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol (1985), 2021. PMID 34351816
• Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging (Albany NY), 2020. PMID 32182209
• Plasma mitochondrial derived peptides MOTS-c and SHLP2 positively associate with android and liver fat in people without diabetes. Biochim Biophys Acta Gen Subj, 2021. PMID 34419510
• MOTS-C levels ın ındividuals with and without obesity and ıts association with ınflammation, insulin resistance and endothelial dysfunction. Arch Endocrinol Metab, 2025. PMID 41004666

This article is for educational and research purposes only and is not medical advice.