Mitochondrial Peptide / SubQ / 5-10mg weekly
Mots-c*
MOTS-c was found in 2015 by searching the mitochondrial genome for short reading frames, after humanin proved that a mitochondrion could encode a signaling peptide at all. Almost everything known about it is still mouse and cell work: an analogue completed an early-phase trial in 2021 without publishing results, and the peptide itself reached people through the research-chemical market rather than through any trial.
In plain words
MOTS-c is a very short peptide whose instructions are written in mitochondrial DNA, the small separate genome inside the cell's power plants, and it was only described in 2015. It is talked about as an exercise mimic because in cells and mice it switches on AMPK, the same energy-sensing switch that exercise and the diabetes drug metformin act on, and because injected mice ran longer and handled blood sugar better. Almost all of that is animal and cell work. In people the peptide has been measured, not given: exercise makes the body's own MOTS-c rise sharply and briefly, and blood levels are lower in diagnosed diabetes but higher in metabolic syndrome without diabetes, so the human observational studies disagree about which way the level even moves, which is a reason to be careful with any deficiency framing. No published trial has given the native peptide to a person, no human pharmacokinetic study of it has been published, and it is approved nowhere, so it reaches people only through the research-chemical market. The mouse doses behind the striking results are also far larger than what people report using, once scaled for body size, so those results cannot be assumed to carry over.
At a glance
| Half-life | 0.5 days |
|---|---|
| Tmax | 0.042 days |
| Route(s) | SubQ |
| Published dosing range | 5-10mg weekly |
| Vial strengths | 10, 5, 20 mg |
Reference data from the DosePlot canon -- not a protocol recommendation.
Serum curve
Single 7.5 mg dose by SubQ, rendered from the same engine that powers the interactive chart. Relative levels, not lab values.
What does the evidence show?
Two things are labeled separately here because they answer different questions. The tier is how a study was built. The distance chips are whether that study touched this molecule, by this route, in a population resembling the reader. A randomized trial of a different molecule keeps its tier and still says nothing about this compound.
| Finding | Tier | Distance from use | Study |
|---|---|---|---|
| MOTS-c acts on the folate cycle, not on a hormone receptor. In cells, it depletes 5-methyl-tetrahydrofolate, the most abundant activated form of folate, which blocks de novo purine synthesis and backs up the intermediate AICAR to more than twenty times control levels. AICAR is a known activator of AMPK, and MOTS-c treatment produced the expected phosphorylation of AMPK-alpha at Thr172. Skeletal muscle appears to be the primary target tissue. All of this is cell and mouse work. | preclinical | not recorded | Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.Cell Metabolism 21(3):443-454, 2015 |
| The mouse results come from two different doses. At 0.5 mg/kg/day intraperitoneally for 8 weeks, MOTS-c prevented obesity in CD-1 mice on a 60 percent fat diet with caloric intake identical between groups, prevented the hyperinsulinemia that diet produces, and raised AMPK phosphorylation and GLUT4 levels in skeletal muscle; three weeks at the same dose raised the respiratory exchange ratio, indicating more glucose use. The insulin-resistance results are a separate protocol at ten times that dose: 5 mg/kg/day intraperitoneally for 7 days raised the glucose infusion rate in a hyperinsulinemic-euglycemic clamp by about 30 percent in high-fat-fed mice, and restored insulin-stimulated glucose uptake into the soleus muscle of 12-month-old mice to levels comparable to 3-month-old animals. Every route here is intraperitoneal and every schedule daily; neither matches how the peptide is used in people. | preclinical | not recorded | Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.Cell Metabolism 21(3):443-454, 2015 |
| The endurance findings are in mice and the doses are large. Two weeks of 15 mg/kg/day intraperitoneal MOTS-c let 22-month-old mice run about twice as long and 2.16 times as far on a treadmill, and 17 percent of treated old mice reached the fastest stage against none of the untreated ones. A late-life intermittent schedule (3 times weekly, 15 mg/kg/day, begun at 23.5 months) improved grip strength, stride length, and a 60-second walking test near end of life. | preclinical | not recorded | Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.Nature Communications 12(1):470, 2021 |
| Exercise raises the body's own MOTS-c, sharply and briefly. Ten sedentary healthy young men (mean age 24.5 years, mean BMI 24.1) did ten 60-second cycling intervals at peak power with biopsies of the vastus lateralis before, immediately after, and after four hours of rest. Muscle MOTS-c rose 11.9-fold immediately after exercise. Circulating MOTS-c rose 1.6-fold during the session and 1.5-fold just after, then returned to baseline within the four-hour rest. This is a measurement of endogenous peptide in people who exercised. Nobody in the study was injected with anything. | clinical | not recorded | Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.Nature Communications 12(1):470, 2021 |
| The strongest human evidence that MOTS-c matters is genetic rather than interventional. An Asian-specific mitochondrial variant, m.1382A>C, swaps the lysine at position 14 of the peptide for glutamine. Across three cohorts totaling 27,527 people, men carrying the C allele had a higher prevalence of type 2 diabetes and women did not, and in one cohort the association appeared only in men in the lowest third of physical activity. In mice, the altered K14Q peptide failed to reproduce the weight and glucose-tolerance effects of the normal sequence. | clinical | not recorded | Zempo H, Kim SJ, Fuku N, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.Aging (Albany NY) 13(2):1692-1717, 2021 |
| Blood levels of MOTS-c are lower in established type 2 diabetes. In 225 people sorted into normal, prediabetic, well-controlled and poorly controlled diabetic groups, serum MOTS-c was significantly lower in the diabetic subjects than in controls (p less than 0.007) and correlated negatively with HbA1c and fasting glucose. This is a cross-sectional association. It does not establish that low MOTS-c causes the disease, and it does not test whether raising it changes anything. | clinical | not recorded | Ramanjaneya M, Bettahi I, Jerobin J, et al. Mitochondrial-derived peptides are down regulated in diabetes subjects.Frontiers in Endocrinology 10:331, 2019 |
| In people without diabetes the association runs the other way. All 125 Chinese participants (91 male, 34 female) had DXA scans, and plasma MOTS-c was higher, not lower, in the 26 who met metabolic syndrome criteria; android fat raised the level more than whole body fat did. The liver-fat finding rests on a smaller and different group: MRI and spectroscopy were done only on the 34 Chinese women plus 34 additional European Caucasian women, so the liver measurements are all-female and 68 people, not 125. The authors read the pattern as a stress signal: mitochondrial peptides rise when the liver is under metabolic load. Taken with the diabetes data above, the human observational literature disagrees with itself about which direction the level moves, which is a reason to treat any deficiency framing with caution. | clinical | not recorded | Sequeira IR, Woodhead JST, Chan A, et al. Plasma mitochondrial derived peptides MOTS-c and SHLP2 positively associate with android and liver fat in people without diabetes.Biochimica et Biophysica Acta General Subjects 1865(11):129991, 2021 |
| Reported community use is subcutaneous, in the 5 to 10 mg per week range recorded in DosePlot's reference dosing range, sometimes split into smaller injections across the week and often timed near training. Reported effects center on endurance and perceived recovery. No published trial has given the native peptide to people, so these uncontrolled reports are the only published description of what injected MOTS-c does in humans. | anecdotal | not recorded | community reports aggregated from reddit, MESO-Rx, and similar forumsno study |
How did it get here?
- preclinical2015
- An in silico search of the human 12S ribosomal RNA gene turns up a 51-base reading frame that translates to a 16-amino-acid peptide, MRWQEMGYIFYPRKLR, deposited as GenBank KP715230. It is named MOTS-c, for mitochondrial open reading frame of the twelve S ribosomal RNA type-c. The same paper reports the folate-AICAR-AMPK mechanism and the mouse obesity and insulin-sensitivity results, and notes the peptide is highly conserved across 14 species, especially its first 11 residues. Later the same year a short Aging Cell paper proposes that m.1382A>C, a mitochondrial variant inside the MOTS-c reading frame found almost only in Northeast Asian populations, might be one mechanism behind Japanese longevity. That hypothesis starts the human genetic thread, and it takes six more years to be tested at scale.
- preclinical2018
- MOTS-c is shown to move into the nucleus under glucose restriction and regulate nuclear genes there, in an AMPK-dependent way, including antioxidant-response-element genes through the transcription factor NRF2. This was the first demonstration that a peptide written in mitochondrial DNA regulates the nuclear genome, rather than only the reverse.
- first-human2018-2021
- A modified MOTS-c analogue, CB4211, becomes the first molecule in this family given to people in a registered trial: a Phase 1a/1b study, listed on the registry as phase 1, in healthy non-obese subjects and in people with non-alcoholic fatty liver disease, 88 participants, registered as NCT03998514 and sponsored by CohBar, started 9 July 2018 and completed 19 April 2021. No peer-reviewed report of its results has appeared, no results are posted to the registry, and the molecule tested was an analogue rather than the native 16-amino-acid sequence. The analogue program went no further, and no interventional trial giving the native peptide to people has appeared on the public registry since.
- preclinical2021
- Two papers land in the same month. One shows that exercise raises endogenous MOTS-c in human muscle and blood and that the peptide improves treadmill performance in young, middle-aged and old mice. The other tests the 2015 longevity hypothesis in 27,527 people and finds the variant associated with type 2 diabetes in men, interacting with how little they move. Neither gives the peptide to a person.
- grey-marketafter 2015, start year not documented
- MOTS-c enters the research-peptide market as a lyophilized powder sold for subcutaneous use. No citable record fixes when the listings began or what drove them, only that they cannot predate the 2015 description of the peptide, so no start year can be fixed, only a range. For the decade that followed, this was the entire route by which the peptide reached human bodies. There is no approval anywhere, no prescription product, no published human dosing study, and no regulatory review of the material being sold, so the reference points a buyer has are a certificate of analysis from the seller and other users' reports.
How is it made?
Production happens in three stages.
1. Building the chain. At 16 residues MOTS-c is built chemically rather than grown in cells. The C-terminal arginine is anchored to a resin bead and the other 15 added one at a time, working backwards to the N-terminal methionine. Every cycle is the same three steps: uncap the chain end, couple the next protected amino acid, wash the excess away. Sixteen residues means sixteen cycles, and a cycle that couples 99 percent still leaves some chains missing a residue.
2. Cleavage and purification. A strong acid mixture cuts the chain off the resin and strips the side-chain protecting groups at once. The crude material is precipitated, then separated on a reverse-phase column. Two impurities matter for this sequence: deletion chains from an incomplete cycle, and oxidized methionine. MOTS-c carries methionine at positions 1 and 6, and methionine takes up oxygen readily. The oxidized peptide is 16 mass units heavier and looks identical in the vial, so mass spectrometry is what tells them apart.
3. Filling. The purified peptide is dissolved, sterile-filtered, dispensed into vials and freeze-dried to a white cake, reconstituted before use. Regulated manufacture tests each lot for identity, purity, sterility, endotoxin, and peptide content, the last because the powder is never pure peptide: residual salt and water inflate the gross weight. The synthesis chemistry is ordinary. Sterile fill, endotoxin testing and honest peptide content are what vary outside regulated manufacturing. None of the three can be judged by looking at the vial.
Worth knowing
A mitochondrion cannot read its own MOTS-c gene. Mitochondria use their own genetic code, and in that code the codons AGA and AGG are stop signals rather than arginine. The second codon of the MOTS-c reading frame is AGG. A mitochondrial ribosome starting at the ATG would therefore stop one codon later, and a second AGA sits at codon 13. The transcript has to leave the mitochondrion and be translated in the cytoplasm using the standard genetic code, which is the only way the full 16 residues get made. The peptide is written in one genome and read by the machinery of the other.
Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.Cell Metabolism 21(3):443-454, 2015
The discovery paper compares MOTS-c to methotrexate, and the comparison is the authors' own. Both target the folate cycle, both deplete 5-methyl-tetrahydrofolate, both raise AICAR, both activate AMPK, and both lower mitochondrial respiration. Methotrexate is an antifolate used in cancer and rheumatoid arthritis. The overlap does not make the peptide dangerous by association, but it does place the described mechanism on a well-mapped drug axis with well-known effects rather than on some novel mitochondrial pathway, and it is the reason the paper's discussion raises anti-inflammatory effects as a research direction.
Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.Cell Metabolism 21(3):443-454, 2015
The doses do not line up, and they miss low rather than high. Published mouse protocols ran 0.5 to 15 mg/kg per day by intraperitoneal injection, dosed daily in most experiments and three times weekly in the late-life intermittent one. Converted by body surface area, the standard animal-to-human scaling that divides a mouse dose by 12.3, those become roughly 3 to 98 mg per day for an 80 kg adult, or about 23 to 680 mg per week. The 5 to 10 mg per week in the reference dosing range is therefore about 2 to 140 times below the scaled equivalent of the animal work. Surface-area scaling is a starting-dose heuristic and not a prediction of effect, but the gap is large enough that the mouse results cannot be assumed to carry over.
Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited.FASEB Journal 22(3):659-661, 2008
Reconstitution
Mots-c* ships lyophilized and is mixed before use; the published vial strengths are 10, 5, 20 mg. The water volume you add sets the concentration, not the dose -- the calculator turns a vial size and a water volume into mg/mL, draw volume, and units on an insulin syringe.
Open in the reconstitution calculatorWritten and reviewed by Evan Marlow, developer of DosePlot · Updated 2026-08-27
Not medical advice. DosePlot is an informational tool, not a healthcare provider, and using it creates no provider-patient relationship. Do not start, stop, or change any protocol without the approval of a licensed healthcare professional.
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