MOTS-c
MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame inside the mitochondrial 12S rRNA gene, making it one of the small family of mitochondrial-derived peptides that also includes humanin. Because it is translated from mitochondrial DNA rather than the nuclear genome, it is described as a message sent from the mitochondrion outward; it is detectable in plasma and in skeletal muscle, which the original description identifies as its apparent primary target organ. Pharmacologically it behaves as a metabolic regulator, activating AMPK and shifting glucose and lipid handling in muscle and fat. It holds no marketing authorisation in any jurisdiction. Reviews of the field state that MOTS-c has so far been used only infrequently in disease treatment and that no effective method of applying it in the clinic has been developed; no human study in which MOTS-c itself was administered was identified among the sources cited in this monograph.
Information on this page is provided for laboratory research reference. The compound is not a drug, supplement, or medical product, and is not for human or veterinary use, ingestion, or consumption.
- #171231 · 40 mg98.523%
Each result applies to the tested sample shown, not to every catalog strength or lot.
The best-established action of MOTS-c is metabolic. In cultured cells — both HEK293 cells stably overexpressing MOTS-c and cells treated with the peptide exogenously — it inhibits the folate cycle and the de novo purine biosynthesis tethered to it, so that AICAR accumulates to more than 20-fold the level of control cells, and AICAR in turn activates AMPK; in mice, MOTS-c treatment likewise increases skeletal-muscle AMPK phosphorylation and GLUT4. Under metabolic stress such as glucose restriction, MOTS-c additionally translocates from the mitochondrion to the nucleus in an AMPK-dependent manner, where it regulates genes carrying antioxidant response elements and interacts with stress-responsive transcription factors including NRF2 (NFE2L2); this was reported as the first demonstration that a mitochondrially encoded factor acts on nuclear gene expression. A direct protein binding partner was identified later: MOTS-c binds and activates casein kinase 2 (CK2) in cell-free systems, and suppressing CK2 activity blunts MOTS-c's effects on muscle atrophy and muscle glucose uptake in mice — with the effect being tissue-specific, since systemically administered MOTS-c binds CK2 in both fat and muscle yet stimulates it in muscle while suppressing it in fat. What is not settled is how circulating MOTS-c reaches those intracellular targets; the authors of the exercise/ageing work describe cellular uptake as still under investigation and the entry mechanism of such peptides as largely unclear, so the endocrine framing rests largely on injection experiments in rodents rather than on an identified uptake route.1,3,4,5
Inhibited by MOTS-c. 5-methyl-tetrahydrofolate is depleted and the purine-pathway intermediate AICAR accumulates, reaching levels more than 20-fold higher in MOTS-c-overexpressing HEK293 cells than in control cells; the same shift is seen, to a lesser extent, in cells treated with exogenous MOTS-c.1
Downstream effector, activated indirectly by the accumulated AICAR rather than by MOTS-c binding AMPK itself. AMPK activation is also required for MOTS-c to enter the nucleus.1,3
Direct binding partner. MOTS-c binds and activates CK2 in cell-free systems; the naturally occurring K14Q variant shows reduced CK2 binding, does not activate CK2 and does not elicit MOTS-c's effects.4
Nuclear arm of the mechanism. Following glucose restriction, nuclear MOTS-c regulates a broad set of genes including ARE-carrying genes, and interacts with ARE-regulating stress-responsive transcription factors such as NFE2L2/NRF2.3
Metabolic & weight
In male CD-1 mice on a 60%-fat diet, eight weeks of MOTS-c (0.5 mg/kg/day intraperitoneally) prevented diet-induced obesity at a caloric intake identical to vehicle. In a separate arm — high-fat-fed C57BL/6 mice given 5 mg/kg/day for seven days — hyperinsulinaemic-euglycaemic clamps showed an approximately 30% higher exogenous glucose infusion rate than vehicle; strain, dose and duration all differ from the obesity experiment.1
In a meta-analysis of three cross-sectional Japanese and Hawaiian cohorts totalling 27,527 people (J-MICC, MEC and TMM), men but not women carrying the C allele of the Asian-specific m.1382A>C variant — which substitutes K14Q in MOTS-c — had a higher prevalence of type 2 diabetes than A-allele carriers; within J-MICC the excess was confined to men in the lowest physical-activity tertile. This is an observational genetic association, not an intervention.6
In a cross-sectional case-control study of 40 obese Chinese children and adolescents and 57 non-obese controls, circulating MOTS-c was lower in the obese group (472.61 ± 22.83 versus 561.64 ± 19.19 ng/mL, P < 0.01), a difference driven by boys (465.26 ± 24.53 versus 584.07 ± 21.18 ng/mL, P < 0.001), with no significant difference between girls (P > 0.05).7
In a cross-sectional study of 85 adults — 48 with a body mass index of 30 kg/m² or above and 37 with a body mass index of 18.5–24.9 kg/m² — serum MOTS-c did not differ between the groups (14.33 ± 3.76 versus 13.67 ± 3.44 pg/mL; p = 0.395); in multiple regression only age (inversely) and HOMA-IR (positively) predicted MOTS-c.8
Mitochondrial function
In an uncontrolled single-arm study of 10 sedentary healthy young men performing one bout of high-intensity interval cycling (ten 60-second intervals), skeletal-muscle MOTS-c rose 11.9-fold above the pre-exercise biopsy (P = 0.0098) and remained elevated after four hours of rest, while plasma MOTS-c rose 1.6-fold during exercise and 1.5-fold immediately after, returning to baseline by four hours.5
In 30 adults randomised to 45 minutes of cycling at 70% of estimated VO2max, a resistance-exercise session or no exercise (n = 10 per arm), circulating humanin rose significantly after endurance exercise but not after resistance exercise, while MOTS-c showed only a trend; neither peptide correlated with VO2max, leg strength or muscle mitochondrial DNA copy number.9
In a cross-sectional study of 211 healthy Japanese adults, carriers of the m.1382A>C C allele had a higher proportion of fast-twitch MHC-IIx muscle fibres than A-allele carriers, and across 721 Japanese athletes and 873 ethnicity-matched controls the C allele was most frequent in sprint and power athletes (6.5%), intermediate in controls (5.1%) and least frequent in endurance athletes (2.9%).10
In a secondary analysis of a randomised trial in 49 stage I–III breast cancer survivors assigned to a 16-week aerobic and resistance exercise programme or to standard care, plasma MOTS-c increased significantly from baseline and relative to the usual-care group among the 24 non-Hispanic White participants (p < 0.01) but not among the 25 Hispanic participants (p > 0.01).11
Longevity & cellular ageing
In 22-month-old male C57BL/6N mice, two weeks of daily MOTS-c (15 mg/kg intraperitoneally) increased treadmill running time 2-fold and running distance 2.16-fold versus untreated old controls (P = 0.000002; n = 19 control, n = 18 MOTS-c), and 17% of treated animals reached the final sprint stage compared with none of the controls.5
In male C57BL/6N mice first treated at 23.5 months of age, intermittent MOTS-c (15 mg/kg, three times weekly) produced greater grip strength (P = 0.000078), longer stride length (P = 0.0038) and better 60-second treadmill walking performance (P = 0.0428) at about 30 months than vehicle; a lifespan analysis in the same paper reached only a trend (P = 0.05 until 31.8 months).5
Inflammation & immune
In non-obese diabetic (NOD) mice, MOTS-c treatment ameliorated the development of hyperglycaemia and reduced islet-infiltrating immune cells, and adoptive transfer of T cells from MOTS-c-treated NOD donors significantly decreased diabetes incidence in NOD-SCID recipients; the same paper reports separately that serum MOTS-c was lower in people with type 1 diabetes than in healthy controls.12
Across a cross-sectional cohort of 404 patients with hepatitis B virus infection and 85 healthy controls, serum MOTS-c correlated inversely with HBV DNA (R = −0.71) and separated chronic hepatitis B from healthy controls with an area under the curve of 0.9530, while MOTS-c inhibited HBV replication by 50–70% in the accompanying cell and mouse experiments.13
What investigators recorded alongside the results above, at the rates their papers state.
No dosed human safety data were identified. None of the human studies cited here administered MOTS-c — all are observational cohorts, genetic-association studies or exercise interventions measuring endogenous peptide — so there is no human exposure cohort from which adverse events, tolerability or dose-limiting effects could be reported. The cited review states that MOTS-c has been used only infrequently in disease treatment and that no effective method of applying it in the clinic has been developed.2
Not applicable — no dosed human cohort identified in the cited literature
Amplification of the senescence-associated secretory phenotype. As summarised in this review, humanin and MOTS-c both exacerbated the SASP in cultured senescent cells by stimulating secretion of IL-6, IL-1β, IL-8, IL-10 and TNF-α — the opposite of a senolytic effect, and a plausible pro-inflammatory liability in aged tissue.14
Direction of effect only; no incidence reported
No notable toxicity in the antiviral experiments. Alongside 50–70% inhibition of HBV replication and improved liver function, MOTS-c produced no notable toxicity in vitro or in vivo in the HBV cell and mouse models tested. This is an animal and cell-culture observation, not a human safety assessment.13
Reported as no notable toxicity; no graded findings given
- 1.The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. · Cell metabolism · 2015 · PMID 25738459
- 2.MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. · Frontiers in endocrinology · 2023 · PMID 36761202
- 3.The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. · Cell metabolism · 2018 · PMID 29983246
- 4.MOTS-c modulates skeletal muscle function by directly binding and activating CK2. · iScience · 2024 · PMID 39559755
- 5.MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. · Nature communications · 2021 · PMID 33473109
- 6.A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. · Aging · 2021 · PMID 33468709
- 7.Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance. · Pediatric diabetes · 2018 · PMID 29691953
- 8.MOTS-C levels ın ındividuals with and without obesity and ıts association with ınflammation, insulin resistance and endothelial dysfunction. · Archives of endocrinology and metabolism · 2025 · PMID 41004666
- 9.Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. · Journal of applied physiology (Bethesda, Md. : 1985) · 2021 · PMID 34351816
- 10.The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance. · Biochimica et biophysica acta. General subjects · 2022 · PMID 34728329
- 11.Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors. · Scientific reports · 2021 · PMID 34413391
- 12.Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes. · Cell reports · 2021 · PMID 34320351
- 13.Novel function of MOTS-c in mitochondrial remodelling contributes to its antiviral role during HBV infection. · Gut · 2024 · PMID 37788894
- 14.Mitochondrial-Derived Peptides Exacerbate Senescence. · Rejuvenation research · 2018 · PMID 30058454
- 15.Circulating levels of MOTS-c in patients with breast cancer treated with metformin. · Aging · 2022 · PMID 36490309