MOTS-c

What MOTS-c is

MOTS-c is a small peptide that the body makes on its own. Most of what is known about it comes from cells in a dish and from mice and rats. Human research is limited so far. It covers studies that measure MOTS-c in blood and a few small exercise studies. No randomized trial has given MOTS-c to people.

As of April 2026 it is still an experimental research peptide. The FDA, the EMA and the MHRA have not approved it, and it has no approved medical use in people.

A peptide is a short chain of amino acids, the building blocks of protein. MOTS-c has 16 of them. The name is short for “Mitochondrial Open reading frame of the Twelve S rRNA type-c”. Mitochondria are the parts of a cell that make energy. They carry their own small genome, apart from the main DNA in the cell nucleus. The code for MOTS-c sits there, inside a gene called 12S ribosomal RNA.

MOTS-c belongs to a small but growing group called mitochondrial-derived peptides, or MDPs. Humanin and SHLP1 through SHLP6 are in the same group. Some scientists call them “mitokines”, because they carry signals between parts of a cell and between tissues.

The lab of Professor Pinchas Cohen at the University of Southern California first described MOTS-c in 2015 [1]. The finding changed how scientists think about mitochondria. For years, the mitochondrial genome was thought to code for just a few parts of the cell’s energy chain, plus transfer RNAs and ribosomal RNAs. The 2015 paper showed it also makes peptides that act on metabolism across the body.

Scientists study MOTS-c because, in animals and cells, it acts like a built-in controller of metabolism. Its effects there look like those of exercise. The proposed actions are [1], [9]:

• turning on AMPK (AMP-activated protein kinase), an enzyme that senses how much energy a cell has
• a better response to insulin
• more glucose taken up by cells
• protection from metabolic harm caused by diet

In people, MOTS-c in the blood has been reported to drop with age and to climb quickly after exercise. That makes it a possible marker of metabolic health and of how well mitochondria work [3].

How much research there is

The research has grown a lot since 2015. It still leans on animals and cells.

Question	Answer
Published studies	Several hundred papers since 2015. This guide cites 16 key ones.
What was tested	Cells in a dish, mice and rats in metabolism and heart models, and groups of people who were observed or had blood markers measured
Human data	Blood marker studies, small exercise groups and population gene studies. No randomized trial has given MOTS-c to people
How well the mechanism is backed	Several independent groups confirmed that it turns on AMPK and takes part in mitochondrial stress signals. CK2 was recently named as a protein it binds directly

How it might work

MOTS-c seems to do two jobs. Inside a cell it helps control metabolism. In the blood it acts like a hormone signal. The evidence for this comes mainly from cells in a dish and from rodents. Human blood marker data backs part of it. The picture is still changing, and newer papers have refined or added to some early findings.

Where it comes from

The gene behind MOTS-c is the mitochondrial 12S rRNA gene, also written MT-RNR1. The peptide is read from a short open reading frame, a small stretch of code that a cell can turn into a peptide. That stretch lies in a region once marked as not coding for any peptide [1]. This is part of a wider rethink. Scientists now say the mitochondrial genome codes for at least eight short peptides that have a regulating role [3], [5].

MOTS-c does not stay inside the mitochondrion that made it. Metabolic stress makes it move. Low glucose, low oxygen and exercise are three such stresses. The peptide then travels into the cytosol, the fluid that fills the cell, and on into the nucleus. In the nucleus it has been reported to help control genes that respond to stress [5].

Signals usually run from the nucleus out to the mitochondria. This one runs the other way. For that reason MOTS-c is treated as a model mitokine: a factor coded in mitochondria that matches gene activity in the nucleus to the cell’s energy state.

Mitochondrial DNA is passed down from the mother. So single-letter changes in the MOTS-c code are inherited from her too. Population gene studies have found variants such as m.1382A>C, which alters one amino acid in the peptide (K14Q). These variants appear to change how active MOTS-c is. They have been linked to differences in longevity, in diabetes risk and in muscle performance [4], [11], [13].

The AMPK switch

AMPK is the target named most often in MOTS-c papers. It is a central energy sensor. It turns on when a cell’s ratio of AMP to ATP goes up. Once on, it moves the cell away from building things up (anabolic) and toward breaking things down for fuel (catabolic). Cells then:

• take up more glucose
• burn more fatty acids
• build new mitochondria
• make less fat and less protein

Lee and colleagues wrote the discovery paper. In it, MOTS-c turned on AMPK in skeletal muscle and raised glucose uptake. Mice on a high-fat diet were protected from obesity and insulin resistance [1]. The authors traced the steps in cells. MOTS-c slowed the folate cycle, and with it the making of new purines, which are building blocks of DNA. That let a molecule called AICAR build up. AICAR is known to turn on AMPK.

Later work sharpened this:

• Yang and colleagues, 2021. In mouse skeletal muscle, MOTS-c and exercise worked together through AMPK signals. Levels of PGC-1α went up, insulin resistance went down, and glucose metabolism improved [9].
• Kumagai and colleagues, 2024. This is the newest piece. Structural and biochemical tests showed that MOTS-c binds casein kinase 2 (CK2) and turns it on. That gives MOTS-c a direct protein partner in skeletal muscle. CK2 sits either upstream of AMPK or beside it [12].

Other effects on metabolism

MOTS-c has been reported to change a group of processes that fit an exercise-like pattern [1], [9]:

• better insulin sensitivity
• better glucose disposal in skeletal muscle
• less body fat in animals fed a high-fat diet
• better markers of new mitochondria being built

Muscle shrinks when a limb is held still. In animal models of this, MOTS-c held back fat from moving into the muscle and lowered signals from myostatin, a protein that limits muscle growth. The result was a protective effect in unused muscle [7], [10].

Some authors take a wider view. They place MOTS-c in a network of peptides that respond to age and metabolism, the mitochondrial-derived peptide system. Reviews in The Journal of Clinical Investigation and the American Journal of Physiology-Endocrinology and Metabolism treat MOTS-c, humanin and the SHLPs as linked controls on energy metabolism and healthspan. They do not treat them as separate, stand-alone factors [5], [3].

What the studies found

The published work now runs from discovery biochemistry and rodent metabolism studies to human blood markers, exercise science and animal heart models. Every study cited here was peer reviewed. Their strength differs a great deal. Cell work, rodent models and small human groups do not carry the same weight.

Exercise

Exercise is one of the strongest natural triggers for MOTS-c.

• Exercise raises it in mice. Reynolds and colleagues published in Nature Communications in 2021. They called MOTS-c an exercise-induced regulator, coded in mitochondria, of muscle balance and of the physical decline that comes with age. In mice, both a single bout and long-term training raised MOTS-c in skeletal muscle. Giving mice MOTS-c from outside eased the age-related drop in physical performance [2].
• Exercise raises it in people. The same group tested human volunteers. A single bout of high-intensity exercise raised MOTS-c in their blood. This matched the rodent data. It supports calling MOTS-c an “exerkine”, a factor released in response to exercise [2].
• Link to strength. Domin and colleagues (2023) ran a preliminary human study. Higher serum MOTS-c went with greater lower-body muscle strength. It had no relation to maximal oxygen uptake. That hints at a closer tie to strength than to endurance [14].
• Genes and activity. Zempo and colleagues (2021) looked at the m.1382A>C (K14Q) variant together with physical activity. Male carriers had a higher diabetes risk, but only if they were physically inactive. This fits the idea that MOTS-c carries some of the benefit of exercise [11].
• A direct target. Kumagai and colleagues (2024) found that MOTS-c binds CK2 directly in skeletal muscle. This offers a way to explain how the peptide shapes muscle function after exercise [12].

Blood sugar and insulin

This is the most developed area of MOTS-c research. It centers on insulin sensitivity and glucose disposal.

• The first paper. The 2015 study in Cell Metabolism used mice. MOTS-c improved insulin sensitivity and raised glucose uptake in skeletal muscle. It protected against insulin resistance from age and from a high-fat diet. The cause named was a slowed folate cycle, which led to AMPK turning on [1].
• Aging model. Li and colleagues (2019) gave MOTS-c to mice treated with D-galactose, a sugar used to model aging. Body weight, insulin sensitivity and blood glucose changed only a little. MOTS-c did cut the abnormal fat buildup seen in the liver, belly fat and skin of these mice [8].
• With exercise. Yang and colleagues (2021) found that MOTS-c and exercise training help each other. Together, through AMPK, they improved glucose metabolism, cut insulin resistance and raised PGC-1α in mouse skeletal muscle. This tightened the link between MOTS-c and exercise-like effects [9].
• Gene variant and diabetes. In groups of Asian men, the K14Q variant (m.1382A>C) was tied to a higher risk of type 2 diabetes among those who were sedentary. So a gene change inside the MOTS-c code may shift metabolic risk across a population [11].

Studies in people

No large randomized trial of MOTS-c given as a compound has been published. A few observational and blood marker studies give an early picture.

• Very long life. The m.1382A>C variant is specific to Northeast Asian populations. Fuku and colleagues (2015) proposed that it may add to the unusually long lives seen in Japanese study groups. This makes MOTS-c genetics one candidate reason why human lifespan varies [4].
• Physical function. The 2023 Domin study gave early human data that tie MOTS-c in the blood to lower-body strength. It may be a marker of physical capacity [14].
• Rise after exercise. In the Reynolds study, a single exercise bout raised blood MOTS-c in human volunteers. That supports its use as a marker of how the body responds to exercise [2].
• Genes and lifestyle. The gene and activity work suggests MOTS-c may act together with physical activity to shift metabolic risk in people. The finding could matter for exercise plans fitted to the person [11].

To date, no major Western peer-reviewed journal has published a placebo-controlled, double-blind randomized clinical trial of MOTS-c given from outside the body.

Heart

A small set of animal studies has tested MOTS-c in the heart. Their results agree with each other.

• Diabetic heart disease. Li and colleagues (2022) gave diabetic rats MOTS-c along with exercise. Heart function was restored, by way of NRG1-ErbB signaling being turned on. This points to a heart-protecting role under metabolic stress [6].
• Pressure overload. Zhong and colleagues (2022) put mouse hearts under pressure overload. MOTS-c stopped heart failure from developing. The authors credited preserved mitochondrial function [15].
• Antioxidant defense. Aerobic exercise guards against heart muscle injury in diabetes. Tang and colleagues (2023) showed that an antioxidant defense driven by MOTS-c was part of that protection [16].

All of this is animal data. No human trial has measured heart outcomes.

Aging

• Lower levels with age. Human studies have reported that serum MOTS-c falls as people get older. This fits the wider loss of mitochondrial function seen in aging tissues [1], [2].
• Reversal in old mice. Aging mice had lost physical performance and muscle balance. Giving them MOTS-c improved both. This supports the idea that restoring MOTS-c signals could ease parts of sarcopenia, the muscle loss of old age, and other age-related loss of function [2].
• Unused muscle. In models where muscle was held still or left unused, MOTS-c reduced skeletal muscle wasting. It did so by holding back fat infiltration and myostatin-related signals [7], [10].
• Part of a bigger system. Recent reviews set MOTS-c beside humanin and the SHLPs as an emerging mitokine axis that matters for aging and healthspan. They compare it with other hormone systems that weaken with age [3], [5].

Legal status in the US

• Not FDA approved. MOTS-c has no approval for medical use from the FDA. The same is true of the EMA in Europe and the MHRA in the UK.
• Banned in sport. The World Anti-Doping Agency names MOTS-c on its Prohibited List as an AMPK activator, under class S4.4 (metabolic modulators). It is banned at all times, both in competition and out of it.

Limits of the research

1. Mostly cells and rodents. Most findings come from cell models and from mice and rats. The human observational data agree with that work. Still, nobody has reported a randomized controlled trial of MOTS-c in people that was large enough to give a clear answer.
2. Unknown handling in the body. Nobody has mapped in detail how the human body handles MOTS-c given from outside. Its bioavailability, half-life, spread through tissues and best route are all unknown. Most animal studies inject it into a vein or into the belly cavity. Those dosing plans do not carry over directly to human research.
3. Genes differ by population. The m.1382A>C variant and related mitochondrial variants cluster in certain populations. A person’s genetic background may shape both their own MOTS-c biology and any response to added peptide.
4. Natural is not the same as added. Exercise raises the body’s own MOTS-c, and the body’s own MOTS-c tracks with metabolic health. Neither fact proves that giving people MOTS-c peptide brings the same benefits.
5. No long-term safety data. There are no long human safety studies. Nobody has described what happens when MOTS-c is kept high with a drug for a long time in healthy adults.
6. Quality varies. As with other research peptides, commercial batches differ in purity and in how true they are to the real peptide. A certificate of analysis confirms identity, purity and sterility for lab work. Independent HPLC/MS testing is advised for cell and animal research.

MOTS-c does clear things in mice and in cells. Whether giving it to people helps them has not been put to a trial.

References

Selected peer-reviewed references. Ordered by relevance to this guide.

1. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015;21(3):443–454. DOI: 10.1016/j.cmet.2015.02.009
2. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021;12(1):470. DOI: 10.1038/s41467-020-20790-0
3. Merry TL, Chan A, Woodhead JST, Reynolds JC, Kumagai H, Kim SJ, Lee C. Mitochondrial-derived peptides in energy metabolism. American Journal of Physiology — Endocrinology and Metabolism. 2020;319(4):E659–E666. DOI: 10.1152/ajpendo.00249.2020
4. Fuku N, Pareja-Galeano H, Zempo H, Alis R, Arai Y, Lucia A, Hirose N. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. 2015;14(6):921–923. DOI: 10.1111/acel.12389
5. Miller B, Kim SJ, Kumagai H, Mehta HH, Xiang W, Liu J, Yen K, Cohen P. Mitochondria-derived peptides in aging and healthspan. The Journal of Clinical Investigation. 2022;132(9):e158449. DOI: 10.1172/JCI158449
6. Li S, Wang M, Ma J, Pang X, Yuan J, Pan Y, Fu Y, Laher I. MOTS-c and exercise restore cardiac function by activating NRG1–ErbB signaling in diabetic rats. Frontiers in Endocrinology (Lausanne). 2022;13:812032. DOI: 10.3389/fendo.2022.812032
7. Kumagai H, Miller B, Kim SJ, Leelaprachakul N, Kikuchi N, Yen K, Cohen P. Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration. American Journal of Physiology — Endocrinology and Metabolism. 2024;326(2):E207–E218. DOI: 10.1152/ajpendo.00285.2023
8. Li Q, Lu H, Hu G, Ye Z, Zhai D, Yan Z, Wang L, Xiang A, Lu Z. Earlier changes in mice after D-galactose treatment were improved by mitochondria derived small peptide MOTS-c. Biochemical and Biophysical Research Communications. 2019;513(2):439–445. DOI: 10.1016/j.bbrc.2019.03.194
9. Yang B, Yu Q, Chang B, Guo Q, Xu S, Yi X, Cao S. MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway. Biochimica et Biophysica Acta (BBA) — Molecular Basis of Disease. 2021;1867(6):166126. DOI: 10.1016/j.bbadis.2021.166126
10. Kumagai H, Coelho AR, Wan J, Mehta HH, Yen K, Huang A, Zempo H, Fuku N, Maeda S, Oliveira PJ, Cohen P, Kim SJ. MOTS-c reduces myostatin and muscle atrophy signaling. American Journal of Physiology — Endocrinology and Metabolism. 2021;320(4):E680–E690. DOI: 10.1152/ajpendo.00275.2020
11. Zempo H, Kim SJ, Fuku N, Nishida Y, Higaki Y, Wan J, Yen K, Miller B, Vicinanza R, Miyamoto-Mikami E, Kumagai H, Naito H, Tanaka K, Hara M, Tanaka H, Yamada Y. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692–1717. DOI: 10.18632/aging.202529
12. Kumagai H, Kim SJ, Miller B, Zempo H, Tanisawa K, Natsume T, Lee SH, Wan J, Leelaprachakul N, Tanaka T, Tokuda H, Yamada Y, Shimizu S, Cohen P. MOTS-c modulates skeletal muscle function by directly binding and activating CK2. iScience. 2024;27(12):111212. DOI: 10.1016/j.isci.2024.111212
13. Kumagai H, Natsume T, Kim SJ, Tobina T, Miyamoto-Mikami E, Shiose K, Ichinoseki-Sekine N, Kakigi R, Tsuzuki T, Miller B, Yen K, Murakami H, Miyachi M, Zempo H, Dobashi S, Machida S, Kobayashi H, Naito H, Cohen P, Fuku N. The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance. Biochimica et Biophysica Acta (BBA) — General Subjects. 2022;1866(2):130048. DOI: 10.1016/j.bbagen.2021.130048
14. Domin R, Pytka M, Żolyński M, Niziński J, Rucinski M, Guzik P, Zieliński J, Ruchała M. MOTS-c serum concentration positively correlates with lower-body muscle strength and is not related to maximal oxygen uptake — a preliminary study. International Journal of Molecular Sciences. 2023;24(19):14951. DOI: 10.3390/ijms241914951
15. Zhong P, Peng J, Yuan M, Kong B, Huang H. Mitochondrial derived peptide MOTS-c prevents the development of heart failure under pressure overload conditions in mice. Journal of Cellular and Molecular Medicine. 2022;26(22):5549–5561. DOI: 10.1111/jcmm.17551
16. Tang M, Su Q, Duan Y, Fu Y, Liang M, Pan Y, Yuan J, Wang M, Pang X, Ma J, Laher I, Li S. The role of MOTS-c-mediated antioxidant defense in aerobic exercise alleviating diabetic myocardial injury. Scientific Reports. 2023;13(1):19781. DOI: 10.1038/s41598-023-47073-0