What is MOTS-c? The AMPK and metabolic research so far

What is MOTS-c? It is a peptide just 16 amino acids long, encoded not in the cell's main genome but within a short open reading frame inside the mitochondrial 12S rRNA gene, part of mitochondrial DNA itself ^[1]. The name is short for mitochondrial open reading frame of the 12S rRNA-c, and the paper that first reported it describes MOTS-c as regulating insulin sensitivity and metabolic homeostasis, with its primary target organ appearing to be skeletal muscle ^[1].

MOTS-c belongs to a small family the field calls mitochondrial-derived peptides (MDPs). A 2022 review counts eight published so far: humanin, MOTS-c, and six small humanin-like peptides named SHLP1 through SHLP6 ^[4]. A 2026 review adds that these peptides act both inside the cell that made them and beyond it, engaging receptors or signalling pathways to regulate nuclear gene expression and metabolic adaptation, and describes MOTS-c specifically as a key regulator of metabolic homeostasis and stress adaptation ^[5].

• MOTS-c is 16 amino acids long and was first reported in 2015, identified from a short open reading frame within the mitochondrial 12S rRNA gene ^[1].
• It sits alongside seven other known mitochondrial-derived peptides: humanin and the six small humanin-like peptides, SHLP1 through SHLP6 ^[4].
• Its discovery paper names skeletal muscle as its primary target organ and AMPK activation as its principal cellular action ^[1].

The discovery paper describes MOTS-c's cellular action as inhibiting the folate cycle and its tethered de novo purine biosynthesis, a route that leads to activation of AMPK, the cell's central energy-sensing enzyme ^[1]. In mice, MOTS-c treatment activated AMPK in skeletal muscle and increased expression of the downstream glucose transporter GLUT4, a change the researchers link to improved muscle glucose uptake ^[1], ^[2].

A 2026 study in two distinct transgenic mouse strains reports that MOTS-c augments muscle mitochondrial bioenergetic performance by relying on both AMPK and a second regulator, the transcriptional coactivator PGC-1α ^[3]. The same study reports that MOTS-c treatment lowered mitochondrial reactive oxygen species emission and the protein damage associated with that oxidative stress, without a detectable change in mitochondrial respiratory protein content, which the authors read as evidence for changes intrinsic to the mitochondria rather than a change in how many there are ^[3].

Beyond skeletal muscle, a 2026 review on the liver describes MOTS-c as activating AMPK, regulating nuclear gene expression, suppressing fibrotic and inflammatory signalling, and restoring mitochondrial function in models of metabolic dysfunction-associated steatotic liver disease ^[5]. The same review is candid about the limits of that picture, naming the receptor-mediated signalling networks MOTS-c uses, the crosstalk among mitochondrial, nuclear and cytosolic pathways, and the mechanisms governing how the peptide is trafficked and distributed in the body as questions still open ^[5].

Because MOTS-c is reported to act both inside the cell that made it and on other tissues at a distance, it has been described as a mitochondrial-encoded hormone or a mitochondrial cytokine, a mitokine ^[2].

The 2015 discovery paper reports that MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity ^[1].

A 2021 study measured physical performance directly, in mice of three ages: young, at 2 months; middle-aged, at 12 months; and old, at 22 months ^[2]. MOTS-c significantly enhanced physical performance in all three age groups ^[2]. Treatment begun late in life, at 23.5 months, and given intermittently three times a week, still increased physical capacity and extended healthspan ^[2].

The improvement in running capacity did not track body weight: the study reports no correlation between body weight and running time, and reads the effect as an improvement in whole-body energy metabolism rather than a side effect of weight change ^[2]. It also reports that the duration of treatment was important to enhance performance, which the authors read as a need to reach a certain physiological state with an improved metabolic profile ^[2].

The same 2021 paper reports that MOTS-c regulates nuclear genes related to metabolism and proteostasis, skeletal muscle metabolism, and how myoblasts, the precursor cells of muscle fibres, adapt to metabolic stress ^[2].

The clearest human signal so far is that exercise raises the body's own MOTS-c. In healthy young men cycling on a stationary bike, skeletal muscle MOTS-c rose 11.9-fold after exercise and stayed elevated through a 4-hour rest, while circulating MOTS-c rose 1.6-fold during exercise and 1.5-fold afterwards before returning to its starting level within that same 4-hour window ^[2].

A 2025 study of 85 adults, 48 with a body-mass index of 30 or higher and 37 with a body-mass index of 18.5 to 24.9, measured fasting serum MOTS-c alongside insulin, high-sensitivity C-reactive protein and asymmetric dimethylarginine ^[7]. Serum MOTS-c did not differ between the two groups, 14.33 ± 3.76 pg/mL against 13.67 ± 3.44 pg/mL, but it correlated positively with the HOMA-IR index, and in the study's regression model both age and HOMA-IR predicted MOTS-c levels, falling with age and rising with insulin resistance ^[7].

Two studies looked at MOTS-c in polycystic ovary syndrome and reported different directions. In 121 adolescents aged 12 to 18 with PCOS compared with 125 healthy controls, mean serum MOTS-c was higher in the PCOS group, but the difference did not reach statistical significance, and every participant in both groups carried only the wild-type genotype at the MOTS-c gene's m.1382A>C site ^[8]. In 40 adult women with PCOS compared with 40 matched controls, serum MOTS-c was significantly lower in the PCOS group, 220.2 ± 147.6 pg/mL against 498.3 ± 224.4 pg/mL, and skeletal-muscle MOTS-c measured by Western blot in a subgroup was also lower, 74.2 ± 15.2 against 100.0 ± 8.5 arbitrary units ^[9]. The second study's authors note that an earlier, smaller study had found a numerically lower but not statistically significant level in PCOS, and describe their own result as the first to detect a significant difference ^[9].

In 32 people on peritoneal dialysis, urinary MOTS-c correlated inversely with a marker of oxidative stress, advanced oxidation protein products, and positively with pulse-wave velocity, a measure of arterial stiffness, while MOTS-c in the dialysate correlated inversely with both pulse-wave velocity and blood pressure ^[10]. The study's authors describe the pattern as pointing to a mitochondrial-vascular axis in kidney failure, with higher urinary MOTS-c linked to lower oxidative stress but, in that same cohort, to greater arterial stiffness ^[10].

In 72 adults treated for a heart attack with percutaneous coronary intervention, postoperative peripheral serum MOTS-c was lower in the 34 who developed reperfusion injury than in the 38 who did not, and it emerged as an independent protective factor on multivariate analysis, alongside a favourable pre-procedure blood-flow grade ^[11]. The authors report that MOTS-c predicted injury with an area under the curve of 0.648 on receiver operating characteristic analysis and describe that as a value needing further validation before it could stand alone as a predictor ^[11].

Two clinical programmes touching MOTS-c are registered on ClinicalTrials.gov, and neither has yet published a human interventional result in this guide's evidence ^[6], ^[12].

The first tested CB4211, an analogue of MOTS-c developed by CohBar, in a Phase 1a/1b study: a three-part, randomised, double-blind, placebo-controlled trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending subcutaneous doses, in healthy non-obese subjects and in subjects with nonalcoholic fatty liver disease ^[6]. Its registration lists the study as completed ^[6].

The second is testing MOTS-c itself, rather than an analogue, in a Phase 2a study sponsored by Hudson Biotech: adults with prediabetes and overweight or obesity are randomised 1:1 to investigational MOTS-c or placebo for 12 weeks of treatment, alongside standardised lifestyle counselling, to evaluate whether it improves insulin sensitivity compared with placebo, and participants are followed for safety through week 16 ^[12]. Its registration lists the study's status as recruiting ^[12].

The receptor or receptors MOTS-c acts through are not settled. The 2026 liver-disease review lists defining MOTS-c's receptor-mediated signalling networks, the crosstalk among mitochondrial, nuclear and cytosolic pathways, and how the peptide is trafficked and distributed in the body as questions still to be answered ^[5].

Where the MOTS-c measured in blood after exercise actually comes from is also unresolved: interstitial MOTS-c rose during one-legged exercise in the 2026 mechanism study, yet no change was detected in the arterio-venous difference across the working leg, which the authors read as evidence that skeletal muscle may not be the source of that circulating rise ^[3].

In people, the observational studies in this guide point in different directions: lower MOTS-c in one PCOS cohort and a non-significant rise in another, no difference by obesity status in one study alongside a clear correlation with insulin resistance within it, and none of them, by design, can say whether raising or lowering MOTS-c changes an outcome for a person ^[7], ^[8], ^[9].

MOTS-c and its analogue CB4211 remain under investigation. CB4211's Phase 1a/1b trial is completed and MOTS-c's own Phase 2a trial is recruiting, and neither compound is approved for human use in any country ^[6], ^[12].