MOTS-C
Published research and evidence base
MOTS-c is a 16-amino-acid microprotein encoded within the mitochondrial 12S rRNA gene that acts as a retrograde signalling molecule, with reported effects on AMPK signalling, folate-methionine one-carbon metabolism, and nuclear stress-response gene expression. Interventional data on administered MOTS-c come almost entirely from rodent and cell-culture studies, in which the peptide improved insulin sensitivity, mitochondrial respiration and exercise capacity. Human research to date is observational or genetic: circulating MOTS-c has been measured as a candidate biomarker across metabolic, cardiovascular, renal and reproductive conditions, and a mitochondrial variant in the MOTS-c coding region (m.1382A>C, K14Q) has been associated with type 2 diabetes risk in East Asian men. No controlled clinical trial has tested exogenous MOTS-c administration in humans, so efficacy and safety in people are not established.
- Studies cited
- 15
- Published 2023+
- 12
- Newest paper
- 2026
- Last reviewed
- Aug 2026
Recurring themes in the literature
- AMPK activation
- mitochondrial-derived peptide (mitokine)
- insulin sensitivity and glucose tolerance
- exercise-induced expression and skeletal muscle function
- Nrf2 and oxidative stress signalling
- retrograde mitochondrial-to-nuclear signalling
- circulating biomarker in metabolic and cardiovascular disease
- m.1382A>C (K14Q) mitochondrial polymorphism
- mitochondrial biogenesis and PGC-1alpha
- ageing and physical decline
Compound identifiers
- CAS
- 1627580-64-6
- PubChem
- 146675088
Recommended by an FDA advisory committee.
On 23–24 July 2026 the FDA’s Pharmacy Compounding Advisory Committee considered MOTS-C for the 503A Bulks List and recommended its addition on a reported vote of 7–5 with two abstentions. Recommended on a divided vote, despite there being no interventional human administration study of the compound.
This is not an approval. The committee advises; it does not decide. The recommendation is not binding, the FDA has not completed the rulemaking that would formally change anything, and inclusion on the 503A Bulks List is not equivalent to FDA approval of a drug. The list also governs pharmacy compounding for patients, which is a separate activity from research-use-only supply.
What the July 2026 advisory vote actually did sets out the process, the other compounds heard, and the four things the vote is routinely misreported as meaning.
What MOTS-C is, chemically.
- Molecular formula
- C101H152N28O22S2
- Molecular weight
- 2174.6 g/mol
- CAS number
- 1627580-64-6
- PubChem CID
- 146675088
These figures come from the PubChem record for this compound and describe the free base. Lyophilised peptide is normally supplied as an acetate or trifluoroacetate salt and carries residual water, so the mass of powder in a vial is not the same quantity as the molecular weight above would suggest. Chromatographic purity on a certificate of analysis does not resolve that difference either — how to read a certificate of analysis explains why.
15 published studies.
Ordered by strength of study design, then by recency. Every entry links to its source record so the finding can be checked against the paper rather than taken on our word.
- 01Systematic review2024
The correlation between mitochondrial derived peptide (MDP) and metabolic states: a systematic review and meta-analysis
Zhou Q, et al. · Diabetology & Metabolic Syndrome · Systematic review and meta-analysis of 7 studies, 602 participants
Pooled analysis reported lower circulating MOTS-c concentrations in participants with diabetes or obesity overall, but subgroup analysis showed the direction differed: reduced in diabetes and increased in obesity. The authors noted small study numbers and heterogeneity in assay methods.
- 02Human clinical2026
Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss
Yoon SH, et al. · Journal of Clinical & Translational Endocrinology · Cross-sectional comparison of 22 lean and 32 adults with obesity, with 10 followed after bariatric surgery weight loss
Circulating MOTS-c was higher in adults with obesity and showed a biphasic relationship with HOMA-IR. Levels did not change after surgical weight loss despite improvements in other metabolic measures.
- 03Human clinical2026
Reduced serum and skeletal muscle MOTS c levels in women with polycystic ovary syndrome are associated with mitochondrial dysfunction
Kutuk IS, et al. · Scientific Reports · 40 women with polycystic ovary syndrome versus 40 age- and BMI-matched controls; serum and skeletal muscle sampling
Women with PCOS had lower serum MOTS-c than controls (220.2 versus 498.3 pg/mL) alongside reduced skeletal muscle expression. The findings were correlational and did not test MOTS-c administration.
- 04Human clinical2026
Circulating mitochondrial-derived microproteins at rest and in response to an acute bout of endurance exercise in individuals with cerebral palsy
Horwath O, et al. · Experimental Physiology · Typically developing adults, typically developing adolescents, and adults with cerebral palsy (GMFCS II-IV); acute endurance exercise bout
Resting circulating mitochondrial-derived microprotein levels, including MOTS-c, were comparable between adults with cerebral palsy and typically developing groups despite lower muscle mass and fitness. Acute endurance exercise produced only minimal changes in circulating levels in all groups.
- 05Human clinical2025
Repeated Heat Stress Modulates the Levels of the Mitokines MOTS-C and FGF21 in Active Men during Calf Muscle Immobilization
Elhusseiny R, et al. · Medicine and Science in Sports and Exercise · Randomised controlled trial, 19 physically active men, 2 weeks of calf immobilization with or without repeated heat treatment
Repeated heat treatment during limb immobilization was associated with higher circulating MOTS-c compared with immobilization alone. The trial measured endogenous mitokine responses rather than administering MOTS-c.
- 06Human clinical2025
Circulating Mitochondrial Open Reading Frame of the 12S Ribosomal RNA Type-c Is Higher in Acute Coronary Syndrome
Cao P, et al. · Journal of the American Heart Association · Case-control study, 400 participants: normal controls, unstable angina, acute myocardial infarction
Circulating MOTS-c was higher in acute coronary syndrome than in controls and discriminated cases with a reported sensitivity of 0.890. A MOTS-c to oxidative stress marker ratio was associated with major adverse cardiac events after myocardial infarction.
- 07Human clinical2024
Effects of empagliflozin and dapagliflozin on serum humanin, MOTS-c levels, nitrosative stress, and ferroptosis parameters in diabetic patients with heart failure
Asil H, et al. · European Journal of Pharmacology · 74 patients with diabetes and heart failure receiving SGLT2 inhibitors, 37 healthy controls
SGLT2-inhibitor treatment was associated with significantly higher serum MOTS-c levels and reduced nitrosative stress and ferroptosis markers relative to baseline. The study measured endogenous MOTS-c as a response marker and did not administer the peptide.
- 08Human clinical2021
A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c
Zempo H, et al. · Aging (Albany NY) · Meta-analysis of three East Asian cohorts (J-MICC, Multiethnic Cohort, Tohoku Medical Megabank), n = 27,527; plus mouse and in vitro work
The East-Asian-specific m.1382A>C variant, which produces a K14Q substitution in MOTS-c, was associated with higher type 2 diabetes prevalence in men but not women, with the association concentrated in men with low physical activity. K14Q-MOTS-c showed diminished insulin-sensitising activity in vitro and in high-fat-fed mice.
- 09Animal in vivo2026
MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner
Gudiksen A, et al. · Free Radical Biology and Medicine · Two transgenic mouse strains (PGC-1alpha and AMPK models) given MOTS-c; skeletal muscle mitochondrial bioenergetics
MOTS-c administration improved intrinsic skeletal muscle mitochondrial bioenergetic performance and reduced oxidative stress markers without increasing respiratory protein content. The effects depended on intact PGC-1alpha and AMPK signalling in the mouse models.
- 10Animal in vivo2025
Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes
Kong BS, et al. · Experimental & Molecular Medicine · Aged C57BL/6 mice and non-obese diabetic mice treated with MOTS-c; human serum comparison
MOTS-c treatment reduced markers of pancreatic islet cell senescence and improved glucose intolerance in the mouse models. The authors also reported lower circulating MOTS-c in people with type 2 diabetes than in healthy controls.
- 11Animal in vivo2025
Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion
Feng Y, et al. · Free Radical Biology and Medicine · Endurance-trained versus sedentary mice, with a comparison of marathon runners and sedentary individuals
Endurance training increased MOTS-c secretion and skeletal muscle mitochondrial respiratory function in mice. Human sampling showed higher MOTS-c in trained runners than sedentary participants, an association rather than an intervention result.
- 12Animal in vivo2024
MOTS-c modulates skeletal muscle function by directly binding and activating CK2
Kumagai H, et al. · iScience · Cell-free binding assays, cultured muscle and adipose cells, mouse muscle atrophy models, with human cohort genotype analysis
MOTS-c was shown to bind casein kinase 2 (CK2) directly, activating it in skeletal muscle while suppressing it in adipose tissue. The K14Q variant peptide showed altered activity, and the corresponding genotype was examined for disease association in human cohorts.
- 13Animal in vivo2021
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Reynolds JC, et al. · Nature Communications · Young, middle-aged and old mice given MOTS-c; supporting human exercise sampling
MOTS-c administration improved physical performance in young, middle-aged and old mice and altered muscle metabolic gene expression. In humans, acute exercise was associated with increased endogenous MOTS-c expression in skeletal muscle and plasma.
- 14Animal in vivo2015
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
Lee C, et al. · Cell Metabolism · Mice (high-fat diet and aged), plus cell culture; MOTS-c administration
The paper described MOTS-c as a mitochondrial-encoded peptide that targets the folate-methionine one-carbon cycle and activates AMPK. In mice, MOTS-c administration prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity.
- 15Review2026
Safety and Efficacy of Approved and Unapproved Peptide Therapies for Musculoskeletal Injuries and Athletic Performance
Mendias CL, Awan TM · Sports Medicine · Narrative review of approved and unapproved peptides used in sports medicine, including mitochondrial-derived peptides
The review found that many unapproved peptides, including mitochondrial-derived peptides, show favourable tissue-repair or metabolic outcomes in animal models. It concluded that rigorous human safety and efficacy data for these compounds remain scarce.
What this evidence does not establish.
No randomised controlled trial has administered exogenous MOTS-c to humans, so dosing, pharmacokinetics, long-term safety and any functional benefit in people are unestablished. Human data are limited to observational biomarker associations and one mitochondrial genotype association, and circulating MOTS-c moves in opposite directions across conditions (lower in diabetes, higher in obesity and acute coronary syndrome), so its interpretation as a marker is not settled; assay standardisation is also inconsistent between studies.
Common questions about the research.
- What is MOTS-C?
MOTS-c is a 16-amino-acid mitochondrial-derived peptide encoded by a short open reading frame inside the mitochondrial 12S rRNA gene. It is studied as a retrograde signalling molecule linking mitochondrial status to nuclear gene expression.
- Why is MOTS-C described as an exercise-responsive peptide?
Because endogenous expression tracks with exercise. The cited Nature Communications work reports that exercise induces MOTS-c expression in human skeletal muscle and circulation, which is why the peptide is studied alongside exercise-adaptation pathways such as AMPK.
- How does MOTS-C relate to other mitochondrial-derived peptides?
It sits in the same family as humanin and the SHLP peptides, all encoded within mitochondrial DNA rather than the nuclear genome. The cited reviews compare their signalling roles; MOTS-c is the member most closely associated in the literature with the folate–AICAR–AMPK axis.
Available from our catalog
For research purposes only. Not for human consumption, diagnosis, treatment, or prevention of any condition. Nothing on this page is medical advice, and no study summarised here should be read as a recommendation.